EP4003339A2 - Dopamine receptor d1 agonists and methods of use - Google Patents
Dopamine receptor d1 agonists and methods of useInfo
- Publication number
- EP4003339A2 EP4003339A2 EP20846249.9A EP20846249A EP4003339A2 EP 4003339 A2 EP4003339 A2 EP 4003339A2 EP 20846249 A EP20846249 A EP 20846249A EP 4003339 A2 EP4003339 A2 EP 4003339A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- fused
- compound
- pharmaceutically acceptable
- solvate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 58
- 102100020802 D(1A) dopamine receptor Human genes 0.000 title abstract description 12
- 101000931925 Homo sapiens D(1A) dopamine receptor Proteins 0.000 title abstract description 12
- 239000000556 agonist Substances 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 254
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 283
- 229910052739 hydrogen Inorganic materials 0.000 claims description 232
- 239000001257 hydrogen Substances 0.000 claims description 232
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 191
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 183
- 229910052736 halogen Inorganic materials 0.000 claims description 168
- 150000002367 halogens Chemical group 0.000 claims description 168
- 125000001072 heteroaryl group Chemical group 0.000 claims description 167
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 147
- 150000003839 salts Chemical class 0.000 claims description 136
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 115
- 125000000217 alkyl group Chemical group 0.000 claims description 112
- 239000012453 solvate Substances 0.000 claims description 112
- 125000003118 aryl group Chemical group 0.000 claims description 96
- 150000002431 hydrogen Chemical group 0.000 claims description 94
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 87
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 84
- 125000000304 alkynyl group Chemical group 0.000 claims description 84
- 125000004429 atom Chemical group 0.000 claims description 84
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 83
- 125000003342 alkenyl group Chemical group 0.000 claims description 81
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 81
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 76
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 61
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 47
- 229910052757 nitrogen Inorganic materials 0.000 claims description 45
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 34
- 201000010099 disease Diseases 0.000 claims description 31
- 241000124008 Mammalia Species 0.000 claims description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims description 25
- 210000001519 tissue Anatomy 0.000 claims description 25
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
- 206010016654 Fibrosis Diseases 0.000 claims description 23
- 229910052760 oxygen Inorganic materials 0.000 claims description 23
- 230000004761 fibrosis Effects 0.000 claims description 22
- 230000003176 fibrotic effect Effects 0.000 claims description 22
- 230000007170 pathology Effects 0.000 claims description 22
- 229910052717 sulfur Inorganic materials 0.000 claims description 22
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 18
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 18
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 16
- 230000000694 effects Effects 0.000 claims description 10
- 230000008901 benefit Effects 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 239000000725 suspension Substances 0.000 claims description 9
- 208000029523 Interstitial Lung disease Diseases 0.000 claims description 7
- 239000002775 capsule Substances 0.000 claims description 7
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 7
- 239000006185 dispersion Substances 0.000 claims description 6
- 230000005764 inhibitory process Effects 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 238000001990 intravenous administration Methods 0.000 claims description 4
- 239000006210 lotion Substances 0.000 claims description 4
- 239000002674 ointment Substances 0.000 claims description 4
- 238000007920 subcutaneous administration Methods 0.000 claims description 4
- 206010023421 Kidney fibrosis Diseases 0.000 claims description 3
- 230000009787 cardiac fibrosis Effects 0.000 claims description 3
- 230000002500 effect on skin Effects 0.000 claims description 3
- 239000000839 emulsion Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 210000005228 liver tissue Anatomy 0.000 claims description 3
- 239000006187 pill Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 abstract description 48
- 150000003384 small molecules Chemical class 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 55
- 210000004027 cell Anatomy 0.000 description 49
- -1 - C1-C6 alkyl Chemical group 0.000 description 44
- 239000000243 solution Substances 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 239000003814 drug Substances 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 239000007787 solid Substances 0.000 description 21
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 20
- 210000004072 lung Anatomy 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 19
- 229940079593 drug Drugs 0.000 description 18
- 208000024891 symptom Diseases 0.000 description 17
- 229940002612 prodrug Drugs 0.000 description 16
- 239000000651 prodrug Substances 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 15
- 239000007832 Na2SO4 Substances 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 229910052938 sodium sulfate Inorganic materials 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 210000002950 fibroblast Anatomy 0.000 description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- 108090000623 proteins and genes Proteins 0.000 description 13
- 238000011282 treatment Methods 0.000 description 13
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 11
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000012091 fetal bovine serum Substances 0.000 description 11
- 238000009472 formulation Methods 0.000 description 11
- 208000014674 injury Diseases 0.000 description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 10
- 239000000499 gel Substances 0.000 description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 10
- 239000002953 phosphate buffered saline Substances 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- 239000000872 buffer Substances 0.000 description 9
- 230000006378 damage Effects 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 208000027418 Wounds and injury Diseases 0.000 description 8
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 229940124597 therapeutic agent Drugs 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 230000004071 biological effect Effects 0.000 description 7
- 125000001246 bromo group Chemical group Br* 0.000 description 7
- 125000001309 chloro group Chemical group Cl* 0.000 description 7
- 229940126214 compound 3 Drugs 0.000 description 7
- 150000003840 hydrochlorides Chemical class 0.000 description 7
- 210000000056 organ Anatomy 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- WIOKNIKEOBUQDQ-UHFFFAOYSA-N 4-(1,2,3,4-tetrahydro-2,6-naphthyridin-4-yl)benzene-1,2-diol Chemical compound C1NCC(C2=CN=CC=C12)C=1C=C(C(=CC=1)O)O WIOKNIKEOBUQDQ-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 6
- 239000006145 Eagle's minimal essential medium Substances 0.000 description 6
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 108020004459 Small interfering RNA Proteins 0.000 description 6
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 239000004055 small Interfering RNA Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 125000004434 sulfur atom Chemical group 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 230000008484 agonism Effects 0.000 description 5
- 125000002947 alkylene group Chemical group 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 229960002591 hydroxyproline Drugs 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000002953 preparative HPLC Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 5
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 4
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 4
- ZISWRXJZUKDIOO-UHFFFAOYSA-N 3-(3,4-dimethoxyphenyl)propan-1-ol Chemical compound COC1=CC=C(CCCO)C=C1OC ZISWRXJZUKDIOO-UHFFFAOYSA-N 0.000 description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 229910015845 BBr3 Inorganic materials 0.000 description 4
- 108010006654 Bleomycin Proteins 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 229960001561 bleomycin Drugs 0.000 description 4
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 4
- 239000006285 cell suspension Substances 0.000 description 4
- 230000005754 cellular signaling Effects 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 125000001188 haloalkyl group Chemical group 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 230000030648 nucleus localization Effects 0.000 description 4
- 125000004430 oxygen atom Chemical group O* 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 230000002206 pro-fibrotic effect Effects 0.000 description 4
- 230000000069 prophylactic effect Effects 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 150000003254 radicals Chemical group 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 231100000241 scar Toxicity 0.000 description 4
- 230000037390 scarring Effects 0.000 description 4
- BGOQGUHWXBGXJW-YOEHRIQHSA-N (6as,12br)-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-10,11-diol Chemical compound N1CC2=CC=CC=C2[C@@H]2[C@@H]1CCC1=C2C=C(O)C(O)=C1 BGOQGUHWXBGXJW-YOEHRIQHSA-N 0.000 description 3
- RIRYPMITWNNAEK-UHFFFAOYSA-N 4-(1,2,3,4-tetrahydro-2,7-naphthyridin-4-yl)benzene-1,2-diol Chemical compound C1NCC(C2=CC=NC=C12)C=1C=C(C(=CC=1)O)O RIRYPMITWNNAEK-UHFFFAOYSA-N 0.000 description 3
- FRIGRVALVZSSPT-UHFFFAOYSA-N 4-(3-methyl-5,6,7,8-tetrahydro-1,7-naphthyridin-5-yl)benzene-1,2-diol Chemical compound CC=1C=NC=2CNCC(C=2C=1)C=1C=C(C(=CC=1)O)O FRIGRVALVZSSPT-UHFFFAOYSA-N 0.000 description 3
- 101150008656 COL1A1 gene Proteins 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 3
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 3
- 102000016359 Fibronectins Human genes 0.000 description 3
- 108010067306 Fibronectins Proteins 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000013504 Triton X-100 Substances 0.000 description 3
- 229920004890 Triton X-100 Polymers 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 210000002821 alveolar epithelial cell Anatomy 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 208000019425 cirrhosis of liver Diseases 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 125000002541 furyl group Chemical group 0.000 description 3
- 238000005227 gel permeation chromatography Methods 0.000 description 3
- 125000004474 heteroalkylene group Chemical group 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- WUAXWQRULBZETB-UHFFFAOYSA-N homoveratric acid Chemical compound COC1=CC=C(CC(O)=O)C=C1OC WUAXWQRULBZETB-UHFFFAOYSA-N 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 125000003373 pyrazinyl group Chemical group 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 125000001113 thiadiazolyl group Chemical group 0.000 description 3
- 125000000335 thiazolyl group Chemical group 0.000 description 3
- 230000008719 thickening Effects 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- 208000037816 tissue injury Diseases 0.000 description 3
- 230000002103 transcriptional effect Effects 0.000 description 3
- 230000008733 trauma Effects 0.000 description 3
- YVUAFURUVLLHHU-UHFFFAOYSA-N (6-bromo-2,3-dimethoxyphenyl)methanol Chemical compound COC1=CC=C(Br)C(CO)=C1OC YVUAFURUVLLHHU-UHFFFAOYSA-N 0.000 description 2
- UBXAMKKKHYRJHW-OXQOHEQNSA-N (6aR,12bS)-10,11-dimethoxy-2-methyl-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridin-3-ol Chemical compound COC1=CC2=C([C@H]3C=4C=C(C(=CC=4CN[C@@H]3CC2)O)C)C=C1OC UBXAMKKKHYRJHW-OXQOHEQNSA-N 0.000 description 2
- UBXAMKKKHYRJHW-JXFKEZNVSA-N (6aS,12bR)-10,11-dimethoxy-2-methyl-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridin-3-ol Chemical compound COC1=CC2=C([C@@H]3C=4C=C(C(=CC=4CN[C@H]3CC2)O)C)C=C1OC UBXAMKKKHYRJHW-JXFKEZNVSA-N 0.000 description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- MOZFAOLCMULKCH-UHFFFAOYSA-N 1,2-dimethoxy-4-(3-nitropropyl)benzene Chemical compound COC1=CC=C(CCC[N+]([O-])=O)C=C1OC MOZFAOLCMULKCH-UHFFFAOYSA-N 0.000 description 2
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 2
- VJUPXEKDKUSBCH-UHFFFAOYSA-N 1-[3,4-dimethoxy-2-(methoxymethoxymethyl)phenyl]-6,7-dimethoxy-2-nitro-1,2,3,4-tetrahydronaphthalene Chemical compound COC=1C(=C(C=CC=1OC)C1C(CCC2=CC(=C(C=C12)OC)OC)[N+](=O)[O-])COCOC VJUPXEKDKUSBCH-UHFFFAOYSA-N 0.000 description 2
- BSKPRZYRGQSCJK-UHFFFAOYSA-N 1-bromo-3,4-dimethoxy-2-(methoxymethoxymethyl)benzene Chemical compound COCOCC1=C(Br)C=CC(OC)=C1OC BSKPRZYRGQSCJK-UHFFFAOYSA-N 0.000 description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- ZDWDKOSUGKIFPE-UHFFFAOYSA-N 2-(diethoxymethyl)-3-[1-(3,4-dimethoxyphenyl)-2-nitroethyl]pyridine Chemical compound C(C)OC(C1=NC=CC=C1C(C[N+](=O)[O-])C1=CC(=C(C=C1)OC)OC)OCC ZDWDKOSUGKIFPE-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- HUTAMNYDFXBVIY-UHFFFAOYSA-N 3,4,10,11-tetramethoxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine Chemical compound COC1=C(C=2CNC3CCC4=C(C3C=2C=C1)C=C(C(=C4)OC)OC)OC HUTAMNYDFXBVIY-UHFFFAOYSA-N 0.000 description 2
- LHHKQWQTBCTDQM-UHFFFAOYSA-N 3-(3,4-dimethoxyphenyl)propanoic acid Chemical compound COC1=CC=C(CCC(O)=O)C=C1OC LHHKQWQTBCTDQM-UHFFFAOYSA-N 0.000 description 2
- KVOZECKNJDOELR-UHFFFAOYSA-N 3-bromo-2-(diethoxymethyl)pyridine Chemical compound BrC=1C(=NC=CC1)C(OCC)OCC KVOZECKNJDOELR-UHFFFAOYSA-N 0.000 description 2
- BQJLTBKKFLTXKO-UHFFFAOYSA-N 3-methoxy-4-methylbenzoyl chloride Chemical compound COC1=CC(C(Cl)=O)=CC=C1C BQJLTBKKFLTXKO-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 2
- IHIIZNMYAGFDFK-UHFFFAOYSA-N 4,5-dimethoxy-2-(3-nitropropyl)benzaldehyde Chemical compound COc1cc(CCC[N+]([O-])=O)c(C=O)cc1OC IHIIZNMYAGFDFK-UHFFFAOYSA-N 0.000 description 2
- USJYIVWOWGTOMP-UHFFFAOYSA-N 4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydro-2,6-naphthyridine Chemical compound COC=1C=C(C=CC=1OC)C1CNCC2=CC=NC=C12 USJYIVWOWGTOMP-UHFFFAOYSA-N 0.000 description 2
- FFZBWXVCPJCPSZ-UHFFFAOYSA-N 4-(3,4-dimethoxyphenyl)-2,4-dihydro-1H-2,6-naphthyridin-3-one Chemical compound COC=1C=C(C=CC=1OC)C1C(NCC2=CC=NC=C12)=O FFZBWXVCPJCPSZ-UHFFFAOYSA-N 0.000 description 2
- COWGZRGEFNSWNK-UHFFFAOYSA-N 4-(3-bromopropyl)-1,2-dimethoxybenzene Chemical compound COC1=CC=C(CCCBr)C=C1OC COWGZRGEFNSWNK-UHFFFAOYSA-N 0.000 description 2
- WFJDGMOVWGWTDQ-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydro-1,7-naphthyridin-5-yl)benzene-1,2-diol Chemical compound N1=CC=CC=2C(CNCC1=2)C=1C=C(C(=CC=1)O)O WFJDGMOVWGWTDQ-UHFFFAOYSA-N 0.000 description 2
- GDRVFDDBLLKWRI-UHFFFAOYSA-N 4H-quinolizine Chemical compound C1=CC=CN2CC=CC=C21 GDRVFDDBLLKWRI-UHFFFAOYSA-N 0.000 description 2
- BISGXTVIPRWTBN-UHFFFAOYSA-N 5-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro-1,7-naphthyridine Chemical compound COC=1C=C(C=CC=1OC)C1C=2C=CC=NC=2CNC1 BISGXTVIPRWTBN-UHFFFAOYSA-N 0.000 description 2
- ITQBYUQRNATZMK-UHFFFAOYSA-N 6,7-dimethoxy-3-nitro-1,2-dihydronaphthalene Chemical compound C1CC([N+]([O-])=O)=CC2=C1C=C(OC)C(OC)=C2 ITQBYUQRNATZMK-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical group CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 102000012422 Collagen Type I Human genes 0.000 description 2
- 108010022452 Collagen Type I Proteins 0.000 description 2
- 201000003883 Cystic fibrosis Diseases 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 241000021559 Dicerandra Species 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000792859 Enema Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 230000004655 Hippo pathway Effects 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 235000010654 Melissa officinalis Nutrition 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- HIIXBMFJLGYZBP-UHFFFAOYSA-N N-benzyl-N-(6,7-dimethoxy-3,4-dihydronaphthalen-2-yl)-3-methoxy-4-methylbenzamide Chemical compound C(C1=CC=CC=C1)N(C(C1=CC(=C(C=C1)C)OC)=O)C1=CC2=CC(=C(C=C2CC1)OC)OC HIIXBMFJLGYZBP-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 238000002123 RNA extraction Methods 0.000 description 2
- 238000010240 RT-PCR analysis Methods 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 201000009594 Systemic Scleroderma Diseases 0.000 description 2
- 206010042953 Systemic sclerosis Diseases 0.000 description 2
- 230000035508 accumulation Effects 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 238000000418 atomic force spectrum Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 238000010804 cDNA synthesis Methods 0.000 description 2
- 125000002843 carboxylic acid group Chemical group 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000000326 densiometry Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 239000007920 enema Substances 0.000 description 2
- 229940079360 enema for constipation Drugs 0.000 description 2
- 230000006862 enzymatic digestion Effects 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000003838 furazanyl group Chemical group 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 125000004438 haloalkoxy group Chemical group 0.000 description 2
- 210000004024 hepatic stellate cell Anatomy 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 239000005414 inactive ingredient Substances 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000865 liniment Substances 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- 230000004807 localization Effects 0.000 description 2
- 230000004199 lung function Effects 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- 238000010841 mRNA extraction Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000002826 magnetic-activated cell sorting Methods 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 238000006241 metabolic reaction Methods 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- OPCIERFZRFIKNO-UHFFFAOYSA-N methyl 2-(4-cyanopyridin-3-yl)-2-(3,4-dimethoxyphenyl)acetate Chemical compound C(#N)C1=C(C=NC=C1)C(C(=O)OC)C1=CC(=C(C=C1)OC)OC OPCIERFZRFIKNO-UHFFFAOYSA-N 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- TXXHDPDFNKHHGW-UHFFFAOYSA-N muconic acid Chemical group OC(=O)C=CC=CC(O)=O TXXHDPDFNKHHGW-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- BOTDVJUEXNILKI-UHFFFAOYSA-N n-benzyl-6,7-dimethoxy-3,4-dihydronaphthalen-2-amine Chemical compound C=1C=2C=C(OC)C(OC)=CC=2CCC=1NCC1=CC=CC=C1 BOTDVJUEXNILKI-UHFFFAOYSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229960004378 nintedanib Drugs 0.000 description 2
- XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical compound O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 XZXHXSATPCNXJR-ZIADKAODSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 2
- 230000005937 nuclear translocation Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 2
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 description 2
- 229960003073 pirfenidone Drugs 0.000 description 2
- 229920002401 polyacrylamide Polymers 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical group OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- JUJBNYBVVQSIOU-UHFFFAOYSA-M sodium;4-[2-(4-iodophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].C1=CC([N+](=O)[O-])=CC=C1N1[N+](C=2C=CC(I)=CC=2)=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=N1 JUJBNYBVVQSIOU-UHFFFAOYSA-M 0.000 description 2
- 210000004872 soft tissue Anatomy 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 238000011269 treatment regimen Methods 0.000 description 2
- 125000004306 triazinyl group Chemical group 0.000 description 2
- 125000001425 triazolyl group Chemical group 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 239000003656 tris buffered saline Substances 0.000 description 2
- CRLBBOBKCLYCJK-UHFFFAOYSA-N (2,3-dimethoxyphenyl)methanol Chemical compound COC1=CC=CC(CO)=C1OC CRLBBOBKCLYCJK-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- LJMZHSAIBSEYLH-WBMJQRKESA-N (6aR,12bR)-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-3,4,10,11-tetrol Chemical compound C1=CC(=C(C=2CN[C@@H]3CCC4=C([C@@H]3C1=2)C=C(C(=C4)O)O)O)O LJMZHSAIBSEYLH-WBMJQRKESA-N 0.000 description 1
- XGACUWGTNNEEOI-DYESRHJHSA-N (6aR,12bS)-3,10,11-trimethoxy-2-methyl-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine Chemical compound COC1=CC=2CN[C@@H]3CCC4=C([C@H]3C=2C=C1C)C=C(C(=C4)OC)OC XGACUWGTNNEEOI-DYESRHJHSA-N 0.000 description 1
- BGOQGUHWXBGXJW-RHSMWYFYSA-N (6aR,12bS)-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-10,11-diol Chemical compound N1CC2=CC=CC=C2[C@H]2[C@H]1CCC1=C2C=C(O)C(O)=C1 BGOQGUHWXBGXJW-RHSMWYFYSA-N 0.000 description 1
- XGACUWGTNNEEOI-UWJYYQICSA-N (6aS,12bR)-3,10,11-trimethoxy-2-methyl-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine Chemical compound COC1=CC=2CN[C@H]3CCC4=C([C@@H]3C=2C=C1C)C=C(C(=C4)OC)OC XGACUWGTNNEEOI-UWJYYQICSA-N 0.000 description 1
- VSTVPUJQIGMUQA-LAUBAEHRSA-N (6aS,12bR)-6-butyl-3-chloro-6a,7,8,12b-tetrahydro-5H-benzo[a]phenanthridine-2,10,11-triol Chemical compound CCCCN1Cc2cc(Cl)c(O)cc2[C@@H]2[C@@H]1CCc1cc(O)c(O)cc21 VSTVPUJQIGMUQA-LAUBAEHRSA-N 0.000 description 1
- DUJBUFXUMONRHW-CRAIPNDOSA-N (6ar,12bs)-2-methyl-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-10,11-diol Chemical compound C1CC2=CC(O)=C(O)C=C2[C@@H]2[C@@H]1NCC1=CC=C(C)C=C12 DUJBUFXUMONRHW-CRAIPNDOSA-N 0.000 description 1
- RMDMGQSKVJJQEX-NFBKMPQASA-N (6ar,12bs)-2-phenyl-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-10,11-diol Chemical compound N([C@@H]1CCC=2C=C(C(=CC=2[C@H]1C1=C2)O)O)CC1=CC=C2C1=CC=CC=C1 RMDMGQSKVJJQEX-NFBKMPQASA-N 0.000 description 1
- MOAVPJVJZOZOSE-CRAIPNDOSA-N (6ar,12bs)-3-methyl-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-10,11-diol Chemical compound OC1=C(O)C=C2[C@H]3C4=CC=C(C)C=C4CN[C@@H]3CCC2=C1 MOAVPJVJZOZOSE-CRAIPNDOSA-N 0.000 description 1
- LYRRSOZNQRVMQC-CRAIPNDOSA-N (6ar,12bs)-4-methyl-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-10,11-diol Chemical compound OC1=C(O)C=C2[C@H]3C(C=CC=C4C)=C4CN[C@@H]3CCC2=C1 LYRRSOZNQRVMQC-CRAIPNDOSA-N 0.000 description 1
- CHIBSDMOHJPZGC-RHSMWYFYSA-N (6ar,12bs)-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-2,10,11-triol Chemical compound C1CC2=CC(O)=C(O)C=C2[C@@H]2[C@@H]1NCC1=CC=C(O)C=C12 CHIBSDMOHJPZGC-RHSMWYFYSA-N 0.000 description 1
- DUJBUFXUMONRHW-YJBOKZPZSA-N (6as,12br)-2-methyl-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-10,11-diol Chemical compound C1CC2=CC(O)=C(O)C=C2[C@H]2[C@H]1NCC1=CC=C(C)C=C12 DUJBUFXUMONRHW-YJBOKZPZSA-N 0.000 description 1
- MOAVPJVJZOZOSE-YJBOKZPZSA-N (6as,12br)-3-methyl-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-10,11-diol Chemical compound OC1=C(O)C=C2[C@@H]3C4=CC=C(C)C=C4CN[C@H]3CCC2=C1 MOAVPJVJZOZOSE-YJBOKZPZSA-N 0.000 description 1
- LYRRSOZNQRVMQC-YJBOKZPZSA-N (6as,12br)-4-methyl-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-10,11-diol Chemical compound OC1=C(O)C=C2[C@@H]3C(C=CC=C4C)=C4CN[C@H]3CCC2=C1 LYRRSOZNQRVMQC-YJBOKZPZSA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 1
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 description 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 125000005988 1,1-dioxo-thiomorpholinyl group Chemical group 0.000 description 1
- SYJMYDMKPSZMSB-AATRIKPKSA-N 1,2-dimethoxy-4-[(e)-2-nitroethenyl]benzene Chemical compound COC1=CC=C(\C=C\[N+]([O-])=O)C=C1OC SYJMYDMKPSZMSB-AATRIKPKSA-N 0.000 description 1
- AMMPLVWPWSYRDR-UHFFFAOYSA-N 1-methylbicyclo[2.2.2]oct-2-ene-4-carboxylic acid Chemical compound C1CC2(C(O)=O)CCC1(C)C=C2 AMMPLVWPWSYRDR-UHFFFAOYSA-N 0.000 description 1
- 125000005987 1-oxo-thiomorpholinyl group Chemical group 0.000 description 1
- XHLHPRDBBAGVEG-UHFFFAOYSA-N 1-tetralone Chemical compound C1=CC=C2C(=O)CCCC2=C1 XHLHPRDBBAGVEG-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- UPHOPMSGKZNELG-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carboxylic acid Chemical group C1=CC=C2C(C(=O)O)=C(O)C=CC2=C1 UPHOPMSGKZNELG-UHFFFAOYSA-N 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004638 2-oxopiperazinyl group Chemical group O=C1N(CCNC1)* 0.000 description 1
- 125000004637 2-oxopiperidinyl group Chemical group O=C1N(CCCC1)* 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical group O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- XLZYKTYMLBOINK-UHFFFAOYSA-N 3-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC(C(=O)C=2C=CC(O)=CC=2)=C1 XLZYKTYMLBOINK-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- DCOPXKMVVJNPSW-UHFFFAOYSA-N 3-bromopyridine-2-carbaldehyde Chemical compound BrC1=CC=CN=C1C=O DCOPXKMVVJNPSW-UHFFFAOYSA-N 0.000 description 1
- JLLJPPBGJVCFGG-UHFFFAOYSA-N 3-chloropyridine-4-carbonitrile Chemical compound ClC1=CN=CC=C1C#N JLLJPPBGJVCFGG-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- CEAVPXDEPGAVDA-UHFFFAOYSA-N 3-methoxy-4-methylbenzoic acid Chemical compound COC1=CC(C(O)=O)=CC=C1C CEAVPXDEPGAVDA-UHFFFAOYSA-N 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- BCWKCHYAQQCSCK-UHFFFAOYSA-N 4-(3a,4,5,6,7,7a-hexahydrothieno[2,3-c]pyridin-4-yl)benzene-1,2-diol Chemical compound S1C=CC2C1CNCC2C=1C=C(C(=CC=1)O)O BCWKCHYAQQCSCK-UHFFFAOYSA-N 0.000 description 1
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- 125000005986 4-piperidonyl group Chemical group 0.000 description 1
- BGOQGUHWXBGXJW-UHFFFAOYSA-N 5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-10,11-diol Chemical compound N1CC2=CC=CC=C2C2C1CCC1=C2C=C(O)C(O)=C1 BGOQGUHWXBGXJW-UHFFFAOYSA-N 0.000 description 1
- LJMZHSAIBSEYLH-UHFFFAOYSA-N 5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-3,4,10,11-tetrol Chemical compound C1=CC(=C(C=2CNC3CCC4=C(C3C1=2)C=C(C(=C4)O)O)O)O LJMZHSAIBSEYLH-UHFFFAOYSA-N 0.000 description 1
- KJPMWVKPVCVZNK-UHFFFAOYSA-N 6,7-dimethoxy-3,4-dihydro-1h-naphthalen-2-one Chemical compound C1CC(=O)CC2=C1C=C(OC)C(OC)=C2 KJPMWVKPVCVZNK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 101150020966 Acta2 gene Proteins 0.000 description 1
- 241000531891 Alburnus alburnus Species 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010058029 Arthrofibrosis Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 238000009020 BCA Protein Assay Kit Methods 0.000 description 1
- 238000000035 BCA protein assay Methods 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LGQCVIDIOXSYTF-RDJZCZTQSA-N BrC1=CC2=C([C@@H]3C=4C=C(C=CC4CN[C@H]3CC2)O)C=C1O Chemical compound BrC1=CC2=C([C@@H]3C=4C=C(C=CC4CN[C@H]3CC2)O)C=C1O LGQCVIDIOXSYTF-RDJZCZTQSA-N 0.000 description 1
- LGQCVIDIOXSYTF-NVXWUHKLSA-N BrC1=CC2=C([C@H]3C=4C=C(C=CC4CN[C@@H]3CC2)O)C=C1O Chemical compound BrC1=CC2=C([C@H]3C=4C=C(C=CC4CN[C@@H]3CC2)O)C=C1O LGQCVIDIOXSYTF-NVXWUHKLSA-N 0.000 description 1
- WBKKWRPRXLOBAQ-CRAIPNDOSA-N BrC1=CC=2CN[C@@H]3CCC4=C([C@H]3C2C=C1)C=C(C(=C4)OC)O Chemical compound BrC1=CC=2CN[C@@H]3CCC4=C([C@H]3C2C=C1)C=C(C(=C4)OC)O WBKKWRPRXLOBAQ-CRAIPNDOSA-N 0.000 description 1
- WBKKWRPRXLOBAQ-YJBOKZPZSA-N BrC1=CC=2CN[C@H]3CCC4=C([C@@H]3C=2C=C1)C=C(C(=C4)OC)O Chemical compound BrC1=CC=2CN[C@H]3CCC4=C([C@@H]3C=2C=C1)C=C(C(=C4)OC)O WBKKWRPRXLOBAQ-YJBOKZPZSA-N 0.000 description 1
- FLLGGWOCRNVOFU-CRAIPNDOSA-N BrC=1C=2CN[C@@H]3CCC4=C([C@H]3C=2C=CC=1)C=C(C(=C4)OC)O Chemical compound BrC=1C=2CN[C@@H]3CCC4=C([C@H]3C=2C=CC=1)C=C(C(=C4)OC)O FLLGGWOCRNVOFU-CRAIPNDOSA-N 0.000 description 1
- FLLGGWOCRNVOFU-YJBOKZPZSA-N BrC=1C=2CN[C@H]3CCC4=C([C@@H]3C=2C=CC=1)C=C(C(=C4)OC)O Chemical compound BrC=1C=2CN[C@H]3CCC4=C([C@@H]3C=2C=CC=1)C=C(C(=C4)OC)O FLLGGWOCRNVOFU-YJBOKZPZSA-N 0.000 description 1
- NXKNQINTYLCZFE-RHSMWYFYSA-N BrC=1C=CC=2CN[C@@H]3CCC4=C([C@H]3C2C1)C=C(C(=C4)O)O Chemical compound BrC=1C=CC=2CN[C@@H]3CCC4=C([C@H]3C2C1)C=C(C(=C4)O)O NXKNQINTYLCZFE-RHSMWYFYSA-N 0.000 description 1
- NXKNQINTYLCZFE-YOEHRIQHSA-N BrC=1C=CC=2CN[C@H]3CCC4=C([C@@H]3C=2C=1)C=C(C(=C4)O)O Chemical compound BrC=1C=CC=2CN[C@H]3CCC4=C([C@@H]3C=2C=1)C=C(C(=C4)O)O NXKNQINTYLCZFE-YOEHRIQHSA-N 0.000 description 1
- VEVFPIZAMYYMIF-PZJWPPBQSA-N C(C)N1[C@H]2CCC3=C([C@@H]2C=2C=C(C=C(C2C1)C)OC)C=C(C(=C3)F)O Chemical compound C(C)N1[C@H]2CCC3=C([C@@H]2C=2C=C(C=C(C2C1)C)OC)C=C(C(=C3)F)O VEVFPIZAMYYMIF-PZJWPPBQSA-N 0.000 description 1
- 238000011814 C57BL/6N mouse Methods 0.000 description 1
- NKWGRGQMHHELLH-KSSFIOAISA-N CC=1C(=CC=2CN[C@H]3CCC4=C([C@@H]3C2C1)C=C(C(=C4)O)O)O Chemical compound CC=1C(=CC=2CN[C@H]3CCC4=C([C@@H]3C2C1)C=C(C(=C4)O)O)O NKWGRGQMHHELLH-KSSFIOAISA-N 0.000 description 1
- NOEMMSVBAPAVFE-FPOVZHCZSA-N CCN1Cc2c(C)c(C)ccc2[C@@H]2[C@@H]1CCc1cc(Br)c(O)cc21 Chemical compound CCN1Cc2c(C)c(C)ccc2[C@@H]2[C@@H]1CCc1cc(Br)c(O)cc21 NOEMMSVBAPAVFE-FPOVZHCZSA-N 0.000 description 1
- 101150072801 COL1A2 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 101150091877 Ccn2 gene Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 206010010317 Congenital absence of bile ducts Diseases 0.000 description 1
- 102000015225 Connective Tissue Growth Factor Human genes 0.000 description 1
- 108010039419 Connective Tissue Growth Factor Proteins 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Chemical group OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 101150110160 DRD1 gene Proteins 0.000 description 1
- 102000007260 Deoxyribonuclease I Human genes 0.000 description 1
- 108010008532 Deoxyribonuclease I Proteins 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 208000001708 Dupuytren contracture Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241001125671 Eretmochelys imbricata Species 0.000 description 1
- USLLHAMCPDTTOB-YOEHRIQHSA-N FC1=CC=2CN[C@H]3CCC4=C([C@@H]3C=2C=C1)C=C(C(=C4)O)O Chemical compound FC1=CC=2CN[C@H]3CCC4=C([C@@H]3C=2C=C1)C=C(C(=C4)O)O USLLHAMCPDTTOB-YOEHRIQHSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010061431 Glial scar Diseases 0.000 description 1
- 206010018341 Gliosis Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Chemical group OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 208000024934 IgG4-related mediastinitis Diseases 0.000 description 1
- 208000014919 IgG4-related retroperitoneal fibrosis Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000002260 Keloid Diseases 0.000 description 1
- 206010023330 Keloid scar Diseases 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical group OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 108010052014 Liberase Proteins 0.000 description 1
- 239000012098 Lipofectamine RNAiMAX Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000002805 Mediastinal fibrosis Diseases 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- TXXHDPDFNKHHGW-CCAGOZQPSA-N Muconic acid Chemical group OC(=O)\C=C/C=C\C(O)=O TXXHDPDFNKHHGW-CCAGOZQPSA-N 0.000 description 1
- 101100319891 Mus musculus Yap1 gene Proteins 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000003510 Nephrogenic Fibrosing Dermopathy Diseases 0.000 description 1
- 206010067467 Nephrogenic systemic fibrosis Diseases 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- 238000000636 Northern blotting Methods 0.000 description 1
- 208000004362 Penile Induration Diseases 0.000 description 1
- 206010034464 Periarthritis Diseases 0.000 description 1
- 208000020758 Peyronie disease Diseases 0.000 description 1
- 229940122907 Phosphatase inhibitor Drugs 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010036805 Progressive massive fibrosis Diseases 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000012083 RIPA buffer Substances 0.000 description 1
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 206010038748 Restrictive cardiomyopathy Diseases 0.000 description 1
- 206010038979 Retroperitoneal fibrosis Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 102000013814 Wnt Human genes 0.000 description 1
- WAWOVBDESDLCJV-UHFFFAOYSA-N [6-(2-amino-6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-2,3-dimethoxyphenyl]methanol Chemical compound NC1C(C2=CC(=C(C=C2CC1)OC)OC)C1=CC=C(C(=C1CO)OC)OC WAWOVBDESDLCJV-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 125000005360 alkyl sulfoxide group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 210000004727 amygdala Anatomy 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- 125000005362 aryl sulfone group Chemical group 0.000 description 1
- 125000005361 aryl sulfoxide group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000000732 arylene group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 239000010425 asbestos Substances 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 238000004630 atomic force microscopy Methods 0.000 description 1
- 230000001746 atrial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 201000005271 biliary atresia Diseases 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- JAMFGQBENKSWOF-UHFFFAOYSA-N bromo(methoxy)methane Chemical compound COCBr JAMFGQBENKSWOF-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 238000013262 cAMP assay Methods 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001722 carbon compounds Chemical class 0.000 description 1
- 210000001054 cardiac fibroblast Anatomy 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- VDQQXEISLMTGAB-UHFFFAOYSA-N chloramine T Chemical compound [Na+].CC1=CC=C(S(=O)(=O)[N-]Cl)C=C1 VDQQXEISLMTGAB-UHFFFAOYSA-N 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 229940126523 co-drug Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000005507 decahydroisoquinolyl group Chemical group 0.000 description 1
- 125000004855 decalinyl group Chemical group C1(CCCC2CCCCC12)* 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- GRTGGSXWHGKRSB-UHFFFAOYSA-N dichloromethyl methyl ether Chemical compound COC(Cl)Cl GRTGGSXWHGKRSB-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical group CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229960001149 dopamine hydrochloride Drugs 0.000 description 1
- 210000001029 dorsal striatum Anatomy 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 201000010048 endomyocardial fibrosis Diseases 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- HJUFTIJOISQSKQ-UHFFFAOYSA-N fenoxycarb Chemical compound C1=CC(OCCNC(=O)OCC)=CC=C1OC1=CC=CC=C1 HJUFTIJOISQSKQ-UHFFFAOYSA-N 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000009368 gene silencing by RNA Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000000174 gluconic acid Chemical group 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Chemical group 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 210000005003 heart tissue Anatomy 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 230000006951 hyperphosphorylation Effects 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 238000010820 immunofluorescence microscopy Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000007901 in situ hybridization Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000007373 indentation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 230000037427 ion transport Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 210000001117 keloid Anatomy 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 210000004924 lung microvascular endothelial cell Anatomy 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000001370 mediastinum Anatomy 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- DILOFCBIBDMHAY-UHFFFAOYSA-N methyl 2-(3,4-dimethoxyphenyl)acetate Chemical compound COC(=O)CC1=CC=C(OC)C(OC)=C1 DILOFCBIBDMHAY-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 239000011325 microbead Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 210000001009 nucleus accumben Anatomy 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical group CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Chemical group CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000005060 octahydroindolyl group Chemical group N1(CCC2CCCCC12)* 0.000 description 1
- 125000005061 octahydroisoindolyl group Chemical group C1(NCC2CCCCC12)* 0.000 description 1
- 210000001010 olfactory tubercle Anatomy 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 229940100691 oral capsule Drugs 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 230000021368 organ growth Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Chemical group OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000007331 pathological accumulation Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229940023488 pill Drugs 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 238000000164 protein isolation Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000000541 pulsatile effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 210000002637 putamen Anatomy 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000011536 re-plating Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 210000000574 retroperitoneal space Anatomy 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229910052895 riebeckite Inorganic materials 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 239000012487 rinsing solution Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Chemical group 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 210000001103 thalamus Anatomy 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000005985 thienyl[1,3]dithianyl group Chemical group 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 230000025934 tissue morphogenesis Effects 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 239000006211 transdermal dosage form Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000001030 ventral striatum Anatomy 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/18—Ring systems of four or more rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
- A61K9/4825—Proteins, e.g. gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention generally relates to compounds that inhibit YAP/TAZ in fibroblasts, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with fibrotic disease.
- Fibrotic diseases including tissue fibrosis across all organs, affects a vast population of people. In the U.S. alone, over half a million people are affected by liver and lung fibrosis. These diseases remain very challenging to treat clinically. In examples such as idiopathic pulmonary fibrosis (IPF) and scleroderma, therapeutic options are extremely limited. In fact, for this group of diseases, the five-year survival rate can be as bleak as many late stage aggressive cancers. BRIEF SUMMARY OF THE INVENTION
- Described herein are small molecule agonists of dopamine receptor D1 that inhibit YAP/TAZ.
- X 2 is N or CR 5 ;
- X 3 is N or CR 6 ;
- X 4 is N or CR 7 ; or X 1 and X 2 are taken together with the intervening atoms to which they are attached form a fused 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 ;
- X 2 and X 3 are taken together with the intervening atoms to which they are attached form a fused 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 ;
- X 3 and X 4 are taken together with the intervening atoms to which they are attached form a fused 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 ;
- n 0, 1, or 2;
- R 1 and R 2 with the intervening atoms to which they are attached form a fused 5-membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 ;
- R 3 is hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6
- alkynyl, or C 1 -C 6 heteroalkyl wherein alkyl, alkenyl, alkynyl and C 1 -C 6 heteroalkyl is unsubstituted or substituted with one, two, or three R 8 ;
- R 4 is hydrogen or C 1 -C 6 alkyl
- each R 5 , R 6 , and R 7 is independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C 1 -C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C1-C6 heteroalkyl is unsubstituted or substituted with one, two, or three R 8 ;
- R 5 and R 6 are taken together with the intervening atoms to which they are attached form a fused 5-membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 ; or R 6 and R 7 are taken together with the intervening atoms to which they are attached form a fused 5-membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 ;
- each R a is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl,
- each R b is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6
- heteroalkyl cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, C1-C6 alkyl, or C1-C6 haloalkyl;
- R b groups on a nitrogen atom are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl which is unsubstituted or substituted with one, two, or three halogen, C1-C6 alkyl, or C1-C6 haloalkyl.
- the compound having the structure of Formula (I) has the structure of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:
- the compound having the structure of Formula (I), has the structure of Formula (III-2), or a pharmaceutically acceptable salt or solvate the thereof:
- the compound having the structure of Formula (I) has the structure of Formula (IIIa), (IIIb), or (IIIc), or a pharmaceutically acceptable salt or solvate the thereof:
- the compound having the structure of Formula (I), has the structure of Formula (IV), or a pharmaceutically acceptable salt or solvate the thereof:
- Formula (IV) is a compound having there structure of Formula (V), or a pharmaceutically acceptable salt or solvate thereof:
- X 5 is N or CR 11 ;
- X 6 is N or CR 12 ;
- X 7 is N or CR 13 ;
- X 5 and X 6 are taken together with the intervening atoms to which they are attached form a fused 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 14 ;
- X 6 and X 7 are taken together with the intervening atoms to which they are attached form a fused 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 14 ;
- n 0, 1, or 2;
- R 4 is hydrogen or C 1 -C 6 alkyl
- R 9 and R 10 with the intervening atoms to which they are attached form a fused 5- membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 14 ; each R 11 , R 12 , and R 13 is independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C 1 - C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 heteroalkyl; wherein alkyl, alkenyl, alkynyl, and C1-C6 heteroalkyl is unsubstituted or substituted with one, two, or three R 14 ; each R 14 is independently halogen, -CN, -OH, -OR a , -
- each R a is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl,
- each R b is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6
- heteroalkyl cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
- R b groups on a nitrogen atom are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl which is unsubstituted or substituted with one, two, or three halogen, C1-C6 alkyl, or C1-C6 haloalkyl.
- the compound having the structure of Formula (V) has the structure of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof:
- the compound having the structure of Formula (VI) has the structure of Formula (VIIa) or (VIIb), or a pharmaceutically acceptable salt or solvate thereof:
- the compound having the structure of Formula (VI) has the structure of Formula (VIIIa), (VIIIb), or (VIIIc), or a pharmaceutically acceptable salt or solvate thereof:
- X 8 is N, O, S, or CR 15 ;
- X 9 is N, O, S, or CR 16 ;
- X 10 is N, O, S, or CR 17 ;
- X 8 , X 9 , and X 10 is O or S;
- R 4 is hydrogen or C 1 -C 6 alkyl; each R 15 , R 16 , and R 17 is independently hydrogen, halogen, -CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C2-C6 alkynyl, or C1-C6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C1-C6 heteroalkyl is unsubstituted or substituted with one, two, or three R 18 ;
- each R 20 , R 21 , and R 22 is independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C 1 - C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C1-C6 heteroalkyl is unsubstituted or substituted with one, two, or three R 19 ; or R 20 and R 21 with the intervening atoms to which they are attached form a fused 5- membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 19 ;
- R 21 and R 22 with the intervening atoms to which they are attached form a fused 5- membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 19 ;
- each R a is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl,
- each R b is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6
- heteroalkyl cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, C1-C6 alkyl, or C1-C6 haloalkyl;
- the compound having the structure of Formula (IX) has the structure of Formula (X), or a pharmaceutically acceptable salt or solvate thereof:
- the compound having the structure of Formula (X) has the structure of Formula (Xa) or (Xb), or a pharmaceutically acceptable salt or solvate thereof:
- the compound having the structure of Formula (X) has the structure of Formula (Xa-1), or a pharmaceutically acceptable salt or solvate thereof:
- a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient.
- the compound disclosed herein, or a pharmaceutically acceptable salt thereof is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration.
- the compound disclosed herein, or a pharmaceutically acceptable salt thereof is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion.
- the fibrotic pathology is interstitial lung disease (ILD).
- the fibrotic pathology is selected from pulmonary fibrosis (PF) and idiopathic pulmonary fibrosis (IPF).
- the fibrotic pathology is selected from liver tissue fibrosis, cardiac fibrosis, kidney fibrosis, and skin tissue fibrosis.
- FIG.1 demonstrates that Compound 3 (left) and Compound 4a (right) selectively inhibit YAP/TAZ nuclear localization in human lung fibroblasts and not in human alveolar epithelial cells.
- FIG.2 shows that Compound 3 at a comcentration of 10 ⁇ M inhibits expression of Col1a1 in precision cut lung slices cultured for 3 days in 24 months aged mice injured with bleomycin.
- IPF Idiopathic Pulmonary Fibrosis
- Tissue fibrosis can occur in multiple vital organs including heart, lung, liver, and kidney. Fibrosis is a progressive process which, through multiple mechanisms, transforms a normal healthy organ into an architecturally and functionally compromised tissue. From a clinical standpoint they represent a serious problem as the therapeutic options remain minimal and the prognosis is generally very poor. Dopamine receptors, which are almost exclusively researched as part of the central nervous system, are actually highly expressed in the periphery as well in select tissues and cells in the body. These receptors signal through downstream pathways which play a major role in tissue fibrosis.
- DRD1 dopamine receptor D1
- DRD1 is a protein that in humans is encoded by the DRD1 gene.
- DRD1 mRNA expression in the central nervous system is highest in the dorsal striatum (caudate and putamen) and ventral striatum (nucleus accumbens and olfactory tubercle).
- DRD1 mRNA expression occurs in the basolateral amygdala, cerebral cortex, septum, thalamus, and hypothalamus.
- YAP and TAZ are transcriptional co-activators and central effectors of the Hippo pathway. Originally identified based on their roles in organ growth and size control during tissue morphogenesis, the Hippo pathway and YAP/TAZ in adult tissues regulate epithelial and endothelial homeostasis, stem cell function and tissue regeneration. An array of mechanical and biochemical signals have been implicated as upstream regulators of YAP and TAZ, with multiple pro-fibrotic stimuli including matrix stiffness, TGFb/SMAD, MRTF/SRF, and WNT signaling all potentially involved.
- G protein coupled receptors are linked to effector proteins from four main classes of G- proteins (e.g., Ga12/13, Gaq/11, Gai/o or Gas).
- G protein coupled receptor stimulates YAP/TAZ nuclear translocation and transcriptional activity.
- G protein coupled receptors inhibit YAP/TAZ nuclear localization and activity via elevation of cAMP.
- activation (agonism) of a G protein coupled receptor results in YAP/TAZ hyper phosphorylation and inactivation under physiological conditions (e.g., agonism of the receptor prevents YAP/TAZ nuclear localization).
- G protein coupled receptor which stimulates YAP/TAZ nuclear translocation and transcriptional activity, which results in expression of profibrotic genes, such as Acta2 (aSMA), Ctgf (Connective tissue growth factor), Fn1 (Fibronectin), Col1a1 (Collagen I), and Col1a2 (Collagen II).
- aSMA Acta2
- Ctgf Connective tissue growth factor
- Fn1 Fibronectin
- Col1a1 Collagen I
- Col1a2 Collagen II
- the present disclosure provides a method of agonizing a G protein coupled receptor in a cell, the method comprising contacting the cell with any one of compounds described herein, or a pharmaceutically acceptable salt thereof.
- the present disclosure provides a method of promoting YAP phosphorylation in a cell, the method comprising contacting the cell with any one of compounds described herein, or a pharmaceutically acceptable salt thereof.
- Described herein are small molecule agonists of dopamine receptor D1 that inhibit YAP/TAZ.
- described herein is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:
- X 1 is N or CR 24 ;
- X 2 is N or CR 5 ;
- X 3 is N or CR 6 ;
- X 4 is N or CR 7 ; or X 1 and X 2 are taken together with the intervening atoms to which they are attached form a fused 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 ;
- X 2 and X 3 are taken together with the intervening atoms to which they are attached form a fused 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 ;
- X 3 and X 4 are taken together with the intervening atoms to which they are attached form a fused 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 ;
- n 0, 1, or 2;
- R 1 and R 2 with the intervening atoms to which they are attached form a fused 5-membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 ;
- R 3 is hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6
- alkynyl, or C 1 -C 6 heteroalkyl wherein alkyl, alkenyl, alkynyl and C 1 -C 6 heteroalkyl is unsubstituted or substituted with one, two, or three R 8 ;
- R 4 is hydrogen or C 1 -C 6 alkyl
- each R 5 , R 6 , R 7 , and R 24 is independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C 1 - C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C1-C6 heteroalkyl is unsubstituted or substituted with one, two, or three R 8 ; or R 5 and R 6 are taken together with the intervening atoms to which they are attached form a fused 5-membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 ; or R 6 and R 7 are taken together with the intervening atoms to which they
- R 5 and R 24 are taken together with the intervening atoms to which they are attached form a fused 5-membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 ;
- each R a is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl,
- each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6
- heteroalkyl cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, C1-C6 alkyl, or C1-C6 haloalkyl;
- R b groups on a nitrogen atom are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl which is unsubstituted or substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- X 2 is N or CR 5 ;
- X 3 is N or CR 6 ;
- X 4 is N or CR 7 ;
- n 0, 1, or 2;
- R 1 and R 2 with the intervening atoms to which they are attached form a fused 5-membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 ;
- R 3 is hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C1-C6 heteroalkyl is unsubstituted or substituted with one, two, or three R 8 ;
- R 4 is hydrogen or C 1 -C 6 alkyl
- each R 5 , R 6 , and R 7 is independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C1-C6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C 1 -C 6 heteroalkyl is unsubstituted or substituted with one, two, or three R 8 ;
- R 5 and R 6 are taken together with the intervening atoms to which they are attached form a fused 5-membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 ; or R 6 and R 7 are taken together with the intervening atoms to which they are attached form a fused 5-membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 ;
- each R a is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl,
- each R b is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6
- heteroalkyl cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, C1-C6 alkyl, or C1-C6 haloalkyl;
- R b groups on a nitrogen atom are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl which is unsubstituted or substituted with one, two, or three halogen, C1-C6 alkyl, or C1-C6 haloalkyl.
- the compound having the structure of Formula (I) or (Ia) is not (6aS,12bR)-2-methyl-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-3,10,11-triol.
- R 1 and R 2 are–OH; R 4 is hydrogen; R 5 is C1-C6 alkyl; and R 6 is OH; then R 7 is not hydrogen.
- R 1 and R 2 are–OH; R 4 is hydrogen; R 5 is–CH 3 ; and R 6 is OH; then R 7 is not hydrogen.
- R 1 and R 2 when R 1 and R 2 are–OH; R 5 is - CH3; R 6 is -OH; and R 7 is hydrogen; then R 4 is not hydrogen.
- R 1 and R 2 when R 1 and R 2 are–OH; R 5 is C1-C6 alkyl; R 6 is -OH; and R 7 is hydrogen; then R 4 is not hydrogen.
- R 1 and R 2 when R 1 and R 2 are–OH; R 4 is hydrogen; R 6 is OH; and R 7 is not hydrogen.
- R 5 is not–CH3.
- the compound having the structure of Formula (I) or (Ia) is not (6aR,12bS)-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-2,10,11-triol.
- R 1 and R 2 are–OH; R 4 is hydrogen; R 6 is OH; then R 5 and R 7 are not both hydrogen.
- the compound having the structure of Formula (I) or (Ia) is not 5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-10,11-diol.
- R 1 and R 2 are–OH and R 4 is hydrogen; at least one of R 5 , R 6 , or R 7 is not hydrogen.
- R 1 and R 2 are–OH and each of R 5 , R 6 , or R 7 is hydrogen; then R 4 not hydrogen.
- R 4 is hydrogen and each of R 5 , R 6 , or R 7 is hydrogen; then one of R 1 or R 2 is not–OH.
- R 1 and R 2 when R 1 and R 2 are–OH; R 4 is hydrogen; then only one of R 5 , R 6 and R 7 is hydrogen. In some embodiments, when R 1 and R 2 are–OH, then at least two of R 5 , R 6 , or R 7 are–OH. In some embodiments, when R 1 and R 2 are–OH and R 4 is hydrogen; then at least two of R 5 , R 6 , or R 7 are–OH.
- the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:
- n 0, 1, or 2;
- R 1 and R 2 with the intervening atoms to which they are attached form a fused 5-membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 ;
- R 3 is hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C1-C6 alkyl, C2-C6 alkenyl, C2-C6
- alkynyl, or C 1 -C 6 heteroalkyl wherein alkyl, alkenyl, alkynyl and C 1 -C 6 heteroalkyl is unsubstituted or substituted with one, two, or three R 8 ;
- R 4 is hydrogen or C1-C6 alkyl
- each R 5 , R 6 , and R 7 is independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C 1 -C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C1-C6 heteroalkyl is unsubstituted or substituted with one, two, or three R 8 ;
- R 5 and R 6 are taken together with the intervening atoms to which they are attached form a fused 5-membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 ;
- R 6 and R 7 are taken together with the intervening atoms to which they are attached form a fused 5-membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 ;
- each R a is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl,
- each R b is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6
- heteroalkyl cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; or two R b groups on a nitrogen atom are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl which is unsubstituted or substituted with one, two, or three halogen, C1-C6 alkyl, or C1-C6 haloalkyl.
- each R 1 and R 2 is independently hydrogen, halogen, - CN, -OH, -OR a , -SH, -SR a , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C 1 -C 6 heteroalkyl is unsubstituted or substituted with one, two, or three R 8 .
- each R 1 and R 2 is independently hydrogen, halogen, - CN, -OH, or -OR a .
- each R 1 and R 2 is independently–Cl, -Br, or–F. In some embodiments, each R 1 and R 2 is independently hydrogen, -OH, or -OR a . In some embodiments, each R 1 and R 2 is independently -OR a . In some embodiments, each R 1 and R 2 is independently–OCH3 or–OCH2CH3. In some embodiments, each R 1 and R 2 is -OH.
- R 1 and R 2 with the intervening atoms to which they are attached form a fused 5-membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 .
- R 1 and R 2 with the intervening atoms to which they are attached form a fused 5-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 .
- R 1 and R 2 with the intervening atoms to which they are attached form a fused 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 .
- R 3 is hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C1-C6 alkyl. In some embodiments, R 3 is hydrogen, halogen, -CN, -OH, -OR a . In some embodiments, each R 1 and R 2 is independently–Cl, -Br, or–F. In some embodiments, R 3 is C 1 -C 6 alkyl. In some embodiments, R 3 is–CH 3 or–CH 2 CH 3 . In some embodiments, R 3 is -OH,–OCH 3 or– OCH2CH3. In some embodiments, R 3 is–Cl, -Br, or–F. In some embodiments, R 3 is hydrogen.
- each R 5 , R 6 , and R 7 is independently hydrogen, halogen, -CN, - OH, -OR a , -SH, -SR a , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C1-C6 heteroalkyl is unsubstituted or substituted with one, two, or three R 8 .
- R 5 is hydrogen; R 6 is -OH, -OR a , or C 1 -C 6 alkyl; and R 7 is hydrogen, -OH, -OR a , or C 1 -C 6 alkyl.
- R 5 is hydrogen; R 6 is–OH or -OR a ; and R 7 is hydrogen, -OH, or -OR a .
- R 5 is hydrogen; R 6 is -OH; and R 7 is - OH.
- R 5 is OH, -OR a , or C 1 -C 6 alkyl; R 6 is hydrogen, -OH, -OR a , or C1-C6 alkyl; and R 7 is hydrogen.
- R 5 is OH or -OR a ; R 6 is hydrogen, -OH, or -OR a ; and R 7 is hydrogen.
- R 5 is OH; R 6 is -OH; and R 7 is hydrogen.
- R 5 and R 6 are taken together with the intervening atoms to which they are attached form a fused 5-membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 .
- R 5 and R 6 are taken together with the intervening atoms to which they are attached form a fused 5-membered ring, that is a fused cycloalkyl, fused heterocycloalkyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 .
- R 5 and R 6 are taken together with the intervening atoms to which they are attached form a fused 6-membered ring, that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 .
- R 6 and R 7 are taken together with the intervening atoms to which they are attached form a fused 5-membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 .
- R 6 and R 7 are taken together with the intervening atoms to which they are attached form a fused 5-membered ring.
- R 6 and R 7 are taken together with the intervening atoms to which they are attached form a fused 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 8 .
- n is 1 or 2. In some embodiments, m is 2. In some
- n is 1. In some embodiments, m is 0.
- the compound having the structure of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (III-1), or a pharmaceutically acceptable salt or solvate thereof:
- X 1 is N; X 2 is CR5; X 3 is CR 6 ; and X 4 is CR 7 .
- X1 is CR 24 ; X 2 is N; X 3 is CR 6 ; and X 4 is CR 7 .
- X 1 is CR 24 ; X 2 is CR 5 ; X 3 is N; and X 4 is CR 7 .
- X 1 and X 2 are taken together with the intervening atoms to which they are attached form a fused 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl or fused heteroaryl, wherein the fused ring is unsubstituted or substituted with one or two R 8 .
- X 2 and X 3 are taken together with the intervening atoms to which they are attached form a fused 6- membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl or fused heteroaryl, wherein the fused ring is unsubstituted or substituted with one or two R 8 .
- X 3 and X 4 are taken together with the intervening atoms to which they are attached form a fused 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl or fused heteroaryl, wherein the fused ring is unsubstituted or substituted with one or two R 8 .
- the compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (III-2), or a pharmaceutically acceptable salt or solvate thereof:
- X 2 is N; X 3 is CR 6 ; and X 4 is CR 7 .
- X 2 is CR 5 ; X 3 is N; and X 4 is CR 7 .
- X 2 is CR 5 ; X 3 is CR 6 ; and X 4 is N.
- X 2 and X 3 are taken together with the intervening atoms to which they are attached form a fused 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl or fused heteroaryl, wherein the fused ring is unsubstituted or substituted with one or two R 8 .
- X 3 and X 4 are taken together with the intervening atoms to which they are attached form a fused 6- membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl or fused heteroaryl, wherein the fused ring is unsubstituted or substituted with one or two R 8 .
- the compound having the structure of Formula (III-1) or (III-2), or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (IIIa), (IIIb), (IIIc), or (IIId), or a pharmaceutically acceptable salt thereof:
- X 2 is N; and R 24 , R 6 and R 7 is each independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C1-C6 heteroalkyl is unsubstituted or substituted with one, two, or three R 8 .
- X 2 is N; and R 24 , R 6 , and R 7 is each independently hydrogen, OH, or -OR a .
- X 2 is N; and R 6 is hydrogen; and R 7 is -OR a .
- X 2 is N; and R 7 is hydrogen; and R 6 is -OR a .
- X 3 is N; and R 24 , R 5 and R 7 is each independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C 1 -C 6 heteroalkyl is unsubstituted or substituted with one, two, or three R 8 .
- X 3 is N; and R 24 , R 5 , and R 7 is each independently hydrogen, OH, or -OR a .
- X 3 is N; and R 5 is hydrogen; and R 7 is -OR a .
- X 3 is N; and R 7 is hydrogen; and R 5 is -OR a .
- X 4 is N; and R 24 , R 5 , and R 6 is each independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C 1 -C 6 heteroalkyl is unsubstituted or substituted with one, two, or three R 8 .
- X 4 is N; and R 24 , R 5 , and R 6 is each independently hydrogen, OH, or -OR a .
- X 3 is N; and R 5 is hydrogen; and R 6 is -OR a .
- X 3 is N; and R 6 is hydrogen; and R 5 is -OR a .
- X 1 is N; and R 5 , R 6 and R 7 is each independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C 1 -C 6 heteroalkyl is unsubstituted or substituted with one, two, or three R 8 .
- X 1 is N; and R 5 , R 6 , and R 7 is each independently hydrogen, OH, or -OR a .
- the compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof:
- X 5 is N or CR 11 ;
- X 6 is N or CR 12 ;
- X 7 is N or CR 13 ;
- X 5 and X 6 are taken together with the intervening atoms to which they are attached form a fused 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 14 ;
- X 6 and X 7 are taken together with the intervening atoms to which they are attached form a fused 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 14 ;
- n 0, 1, or 2;
- R 4 is hydrogen or C 1 -C 6 alkyl
- R 9 and R 10 with the intervening atoms to which they are attached form a fused 5- membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 14 ;
- each R a is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl,
- each R b is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6
- heteroalkyl cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
- R b groups on a nitrogen atom are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl which is unsubstituted or substituted with one, two, or three halogen, C1-C6 alkyl, or C1-C6 haloalkyl.
- X 5 and X 6 are taken together with the intervening atoms to which they are attached form a fused 5-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl or fused heteroaryl, wherein the fused ring is unsubstituted or substituted with one or two R 14 .
- X 5 and X 6 are taken together with the intervening atoms to which they are attached form a fused 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl or fused heteroaryl, wherein the fused ring is unsubstituted or substituted with one or two R 14 .
- X 6 and X 7 are taken together with the intervening atoms to which they are attached form a fused 5-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl or fused heteroaryl, wherein the fused ring is unsubstituted or substituted with one or two R 14 .
- X 6 and X 7 are taken together with the intervening atoms to which they are attached form a fused 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl or fused heteroaryl, wherein the fused ring is unsubstituted or substituted with one or two R 14 .
- X 5 is N or CR 11 ;
- X 6 is N or CR 12 ;
- X 7 is N or CR 13 ;
- n 0, 1, or 2;
- R 4 is hydrogen or C1-C6 alkyl
- R 9 and R 10 with the intervening atoms to which they are attached form a fused 5- membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 14 ;
- each R a is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl,
- each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6
- heteroalkyl cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
- R b groups on a nitrogen atom are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl which is unsubstituted or substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- n is 1 or 2. In some embodiments, n is 2. In some embodiments, n is 1. In some embodiments, n is 0.
- the compound having the structure of Formula (V), or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof:
- X 5 is N or CR 11 ;
- X 6 is N or CR 12 ;
- X 7 is N or CR 13 ;
- R 4 is hydrogen or C1-C6 alkyl
- R 9 and R 10 with the intervening atoms to which they are attached form a fused 5- membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 14 ;
- each R a is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl,
- each R b is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6
- heteroalkyl cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, C1-C6 alkyl, or C1-C6 haloalkyl;
- R b groups on a nitrogen atom are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl which is unsubstituted or substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- each R 9 and R 10 is independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C 1 -C 6 heteroalkyl is unsubstituted or substituted with one, two, or three R 14 .
- each R 9 and R 10 is independently hydrogen, halogen, -CN, -OH, or -OR a .
- each R 9 and R 10 is independently–Cl, -Br, or–F. In some embodiments, each R 9 and R 10 is independently hydrogen, -OH, or -OR a . In some embodiments, each R 9 and R 10 is independently -OR a . In some embodiments, each R 9 and R 10 is independently–OCH 3 or– OCH2CH3. In some embodiments, each R 9 and R 10 is independently -OH.
- R 9 and R 10 with the intervening atoms to which they are attached form a fused 5-membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl or fused heteroaryl, wherein the fused ring is unsubstituted or substituted with one or two R 14 .
- R 9 and R 10 with the intervening atoms to which they are attached form a fused 5-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl or fused heteroaryl, wherein the fused ring is unsubstituted or substituted with one or two R 14 .
- R 9 and R 10 with the intervening atoms to which they are attached form a fused 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl or fused heteroaryl, wherein the fused ring is unsubstituted or substituted with one or two R 15 .
- each R 11 , R 12 , and R 13 is independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C 1 -C 6 heteroalkyl is unsubstituted or substituted with one, two, or three R 14 .
- each R 11 , R 12 , and R 13 is independently C1-C6 alkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl. In some embodiments, each R 11 , R 12 , and R 13 is independently C 1 -C 6 alkyl. In some embodiments, each R 11 , R 12 , and R 13 is independently hydrogen, halogen, -CN, -OH, -OR a . In some embodiments, each R 11 , R 12 , and R 13 is hydrogen.
- X 5 is N; X 6 is CR 12 ; and X 7 is CR 13 .
- R 11 is hydrogen, -OH, -OR a , or C 1 -C 6 alkyl; and R 13 is hydrogen. In some embodiments; R 11 is -OH; and R 13 is hydrogen. In some embodiments; R 11 is hydrogen; and R 13 is hydrogen.
- R 12 is hydrogen, -OH, -OR a , or C 1 -C 6 alkyl; and R 13 is hydrogen. In some embodiments; R 12 is -OH; and R 13 is hydrogen. In some embodiments; R 12 is hydrogen; and R 13 is hydrogen.
- R 11 is hydrogen, -OH, -OR a , or C 1 -C 6 alkyl; and R 12 is hydrogen. In some embodiments; R 11 is -OH; and R 12 is hydrogen. In some embodiments; R 11 is hydrogen; and R 12 is hydrogen.
- the compound having the structure of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (VIIa) or (VIIb), or a pharmaceutically acceptable salt or solvate thereof:
- X 5 is N; X 6 is CR 12 ; and X 7 is CR 13 . In some embodiments, X 5 is CR 11 ; X 6 is N; and X 7 is CR 13 . In some embodiments, X 5 is CR 11 ; X 4 is CR 12 ; and X 7 is N.
- the compound having the structure of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (VIIIa) , (VIIIb), or (VIIIc), or a pharmaceutically acceptable salt or solvate thereof:
- X 5 is N; and R 12 and R 13 is each independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C1-C6 heteroalkyl is unsubstituted or substituted with one, two, or three R 14 .
- X 5 is N; and R 12 and R 13 is each independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C1-C
- X 5 is N; and R 12 is hydrogen; and R 13 is -OR a . In some embodiments, X 5 is N; and R 13 is hydrogen; and R 12 is -OR a .
- X 6 is N; and R 11 and R 13 is each independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C1-C6 heteroalkyl is unsubstituted or substituted with one, two, or three R 14 .
- X 6 is N; and R 11 and R 13 is each independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C1-C
- X 6 is N; and R 11 is hydrogen; and R 13 is -OR a . In some embodiments, X 6 is N; and R 13 is hydrogen; and R 11 is -OR a .
- X 7 is N; and R 11 and R 12 is each independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C1-C6 heteroalkyl is unsubstituted or substituted with one, two, or three R 13 .
- X 7 is N; and R 11 and R 12 is each independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C1-C6 heteroalkyl is unsubstituted
- X 7 is N; and R 11 is hydrogen; and R 12 is -OR a . In some embodiments, X 7 is N; and R 12 is hydrogen; and R 11 is -OR a .
- X 8 is N, O, S, or CR 15 ;
- X 9 is N, O, S, or CR 16 ;
- X 10 is N, O, S, or CR 17 ;
- X 8 , X 9 , and X 10 is O or S;
- R 4 is hydrogen or C 1 -C 6 alkyl
- each R 15 , R 16 , and R 17 is independently hydrogen, halogen, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C1-C6 heteroalkyl is unsubstituted or substituted with one, two, or three R 18 ;
- R 20 and R 21 with the intervening atoms to which they are attached form a fused 5- membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 19 ; or R 21 and R 22 with the intervening atoms to which they are attached form a fused 5- membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 19 ;
- each R a is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl,
- each R b is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6
- heteroalkyl cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, C1-C6 alkyl, or C1-C6 haloalkyl;
- R b groups on a nitrogen atom are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl which is unsubstituted or substituted with one, two, or three halogen, C1-C6 alkyl, or C1-C6 haloalkyl.
- each R 15 , R 16 , and R 17 is independently hydrogen, halogen, -CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C1-C6 heteroalkyl is unsubstituted or substituted with one, two, or three R 18 .
- each R 15 , R 16 , and R 17 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C 1 -C 6 heteroalkyl is unsubstituted or substituted with one, two, or three R 18 .
- each R 15 , R 16 , and R 17 is independently C1-C6 alkyl or C2-C6 alkenyl.
- each R 15 , R 16 , and R 17 is independently C 1 -C 6 alkyl.
- each R 15 , R 16 , and R 17 is independently -CH 3 , - CH2CH3, -(CH2)2CH3, -(CH2)3CH3, or -CH2(CH3)2. In some embodiments, each R 15 , R 16 , and R 17 is independently -(CH2)2CH3, -(CH2)3CH3, or–CH(CH3)2. In some embodiments, each R 15 , R 16 , and R 17 is independently -(CH 2 ) 2 CH 3 . In some embodiments, each R 15 , R 16 , and R 17 is independently -(CH 2 ) 3 CH 3 . In some embodiments, each R 15 , R 16 , and R 17 is independently– CH(CH3)2.
- each R 15 , R 16 , and R 17 is independently hydrogen, halogen, or -CN. In some embodiments, each R 15 , R 16 , and R 17 is independently hydrogen, -Br, -Cl, or -F. In some embodiments, each R 15 , R 16 , and R 17 is independently hydrogen.
- each R 20 , R 21 , and R 22 is independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , C1-C6 alkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C 1 -C 6 heteroalkyl is unsubstituted or substituted with one, two, or three R 19 .
- each R 20 , R 21 , and R 22 is independently hydrogen, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 heteroalkyl.
- each R 20 , R 21 , and R 22 is independently hydrogen, halogen, -CN, -OH, -OR a .
- each R 20 , R 21 , and R 22 is
- each R 20 , R 21 , and R 22 is independently C1-C6 alkyl. In some embodiments, each R 20 , R 21 , and R 22 is independently–CH3, -CH 2 CH 3 , or CH(CH 3 ) 2 . In some embodiments, each R 20 , R 21 , and R 22 is independently–OH or - OCH 3 .
- R 20 and R 21 are independently–OH or–OR a ; and R 22 is hydrogen or halogen. In some embodiments, R 20 and R 21 are independently–OH or–OCH 3 ; and R 22 is hydrogen or halogen. In some embodiments, R 20 and R 21 is–OH; and R 22 is hydrogen. In some embodiments, R 20 and R 21 is–OCH3; and R 22 is hydrogen.
- R 21 and R 22 are independently–OH or–OR a ; and R 20 is hydrogen or halogen. In some embodiments, R 21 and R 22 are independently–OH or–OCH 3 ; and R 20 is hydrogen or halogen. In some embodiments, R 21 and R 22 is–OH; and R 20 is hydrogen. In some embodiments, R 21 and R 22 is–OCH3; and R 20 is hydrogen.
- R 20 and R 22 are independently–OH or–OR a ; and R 21 is hydrogen or halogen. In some embodiments, R 20 and R 22 are independently–OH or–OCH 3 ; and R 21 is hydrogen or halogen. In some embodiments, R 20 and R 22 is–OH; and R 21 is hydrogen. In some embodiments, R 20 and R 22 is–OCH3; and R 21 is hydrogen.
- R 20 and R 21 are taken together with the intervening atoms to which they are attached form a fused 5-membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl or fused heteroaryl, wherein the fused ring is unsubstituted or substituted with one or two R 19 .
- R 20 and R 21 with the intervening atoms to which they are attached form a fused 5-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl or fused heteroaryl, wherein the fused ring is unsubstituted or substituted with one or two R 19 .
- R 20 and R 21 with the intervening atoms to which they are attached form a fused 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl or fused heteroaryl, wherein the fused ring is unsubstituted or substituted with one or two R 19 .
- R 21 and R 22 are taken together with the intervening atoms to which they are attached form a fused 5-membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl or fused heteroaryl, wherein the fused ring is unsubstituted or substituted with one or two R 19 .
- R 21 and R 22 with the intervening atoms to which they are attached form a fused 5-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl or fused heteroaryl, wherein the fused ring is unsubstituted or substituted with one or two R 19 .
- R 21 and R 22 with the intervening atoms to which they are attached form a fused 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl or fused heteroaryl, wherein the fused ring is unsubstituted or substituted with one or two R 19 .
- X 8 is N; X 9 is N; and X 10 is CR 17 .
- X 8 is CR 15 ; X 9 is N; and X 10 is N.
- X 8 is N; X 9 is N; and X 10 is N.
- X 8 is O or S; X 9 is CR 16 ; and X 10 is CR 17 .
- X 8 is S; X 9 is CR 16 ; and X 10 is CR 17 .
- X 8 is CR 15 ; X 9 is CR 16 ; and X 10 is O or S.
- X 8 is CR 15 ; X 9 is CR 16 ; and X 10 is S.
- the compound of Formula (IX) is not 4-(3a,4,5,6,7,7a- hexahydrothieno[2,3-c]pyridin-4-yl)benzene-1,2-diol.
- R 4 when X 10 is S; R 4 is hydrogen; R 20 is hydrogen; and each of R 21 and R 22 is–OH; R 15 is not hydrogen.
- R 15 when X 10 is S; R 4 is hydrogen; R 15 is hydrogen; and R 21 and R 22 are each–OH; R 20 is not hydrogen.
- R 20 is not hydrogen.
- the compound have the structure of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (X), or a pharmaceutically acceptable salt or solvate thereof:
- X 8 is O, S, or CR 15 ;
- X 10 is O, S, or CR 17 ;
- X 8 and X 10 are O or S;
- R 4 is hydrogen or C1-C6 alkyl
- each R 15 and R 17 is independently hydrogen, halogen, -CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C 1 -C 6 heteroalkyl is unsubstituted or substituted with one, two, or three R 18 ;
- each R 15 , R 16 , and R 17 is independently hydrogen, halogen, -CN, - C1-C6 alkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C 1 -C 6 heteroalkyl is unsubstituted or substituted with one, two, or three R 18 ;
- R 20 and R 21 with the intervening atoms to which they are attached form a fused 5- membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 19 ;
- R 21 and R 22 with the intervening atoms to which they are attached form a fused 5- membered or 6-membered ring that is a fused cycloalkyl, fused heterocycloalkyl, fused phenyl, or fused heteroaryl; wherein the fused ring is unsubstituted or substituted with one or two R 18 ;
- each R a is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl,
- each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6
- heteroalkyl cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, C1-C6 alkyl, or C1-C6 haloalkyl;
- R b groups on a nitrogen atom are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl which is unsubstituted or substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- X 8 is O or S; and X 10 is CR 17 . In some embodiments, X 8 is S; and X 10 is CR 17 . In some embodiments, X 8 is CR 15 ; and X 10 is O or S. In some embodiments, X 8 is CR 15 ; and X 10 is S.
- the compound having the structure of Formula (X), or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (Xa) or (Xb), or a pharmaceutically acceptably salt or solvate thereof:
- R 15 is halogen, -CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C1-C6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C1-C6 heteroalkyl is unsubstituted or substituted with one, two, or three R 18 .
- R 15 is C1-C6 alkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl.
- R 15 is C 1 -C 6 alkyl.
- R 15 is–CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , or–CH(CH 3 ) 2 .
- R 15 is -(CH2)2CH3, -(CH2)3CH3, or–CH(CH3)2.
- R 15 is - (CH2)2CH3.
- R 15 is -(CH2)3CH3.
- R 15 is–CH(CH3)2.
- R 17 is halogen, -CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C1-C6 heteroalkyl; wherein alkyl, alkenyl, alkynyl and C1-C6 heteroalkyl is unsubstituted or substituted with one, two, or three R 18 .
- R 17 is C1-C6 alkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl.
- R 17 is C 1 -C 6 alkyl.
- R 17 is–CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, or–CH(CH3)2. In some embodiments, R 17 is -(CH2)2CH3, -(CH2)3CH3, or–CH(CH3)2. In some embodiments, R 17 is - (CH 2 ) 2 CH 3 . In some embodiments, R 17 is -(CH 2 ) 3 CH 3 . In some embodiments, R 17 is–CH(CH 3 ) 2 .
- the compound having the structure of Formula (X), or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (Xa-1), or a pharmaceutically acceptably salt or solvate thereof:
- R 4 is C 1 -C 6 alkyl. In some embodiments, R 4 is -CH 3 ,–CH 2 CH 3 , -(CH2)2CH3, -CH(CH3)CH2CH3, or–CH(CH3)2. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is–CH(CH3)2. In some embodiments R 4 is hydrogen.
- each R 8 , R 14 , R 18 , and R 19 is independently halogen, -CN, -OH, -OR a , -N(R b )2.
- each R 8 , R 14 , R 18 , and R 19 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1- C6 heteroalkyl, or cycloalkyl; wherein each alkyl, heteroalkyl, and cycloalkyl is independently unsubstituted or substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- each R a is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-C6 alkyl(aryl), -C1- C6 alkyl(heteroaryl), -C1-C6 alkyl(cycloalkyl), or -C1-C6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, C1-C6 alkyl, or C1-C6 haloalkyl.
- each R a is independently C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, C1-C6 alkyl, or C1-C6 haloalkyl.
- each R a is independently C 1 -C 6 alkyl or C 1 -C 6 heteroalkyl; wherein the alkyl or heteroalkyl is independently unsubstituted or substituted with one, two, or three halogen, -OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- each R a is independently C1-C6 alkyl; wherein the alkyl is unsubstituted or substituted with one, two, or three halogen.
- each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- each R b is independently hydrogen, C1-C6 alkyl or C1-C6 heteroalkyl; wherein the alkyl or heteroalkyl is independently unsubstituted or substituted with one, two, or three halogen, -OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- each R b is independently C 1 -C 6 alkyl; wherein the alkyl is unsubstituted or substituted with one, two, or three halogen.
- each R b is hydrogen.
- two R b groups on a nitrogen atom are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl which is unsubstituted or substituted with one, two, or three halogen, C1-C6 alkyl, or C1-C6 haloalkyl.
- two R b groups on a nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3- to 7-membered heterocycloalkyl which is unsubstituted or substituted with one, two, or three halogen, C1-C6 alkyl, or C1-C6 haloalkyl.
- two R b groups on a nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocycloalkyl which is unsubstituted or substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- two R b groups on a nitrogen atom are taken together with the nitrogen atom to which they are attached to form pyrrolidine, piperidine, or morpholine which is unsubstituted or substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- two R b groups on a nitrogen atom are taken together with the nitrogen atom to which they are attached to form pyrrolidine, piperidine, or morpholine. Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.
- the compound is a compound selected from Table 1, or a pharmaceutically acceptable salt or solvate thereof.
- the compound is a compound selected from Table 2, or a pharmaceutically acceptable salt or solvate thereof.
- the compound is a compound of Table 3, or a pharmaceutically acceptable salt or solvate thereof.
- Additional compounds include:
- a compound disclosed herein possesses one or more stereocenters and each stereocenter exists independently in either the R or S configuration.
- the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof.
- the compounds and methods provided herein include all cis, trans, syn, anti,
- E
- Z
- compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure enantiomers.
- resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein.
- diastereomers are separated by separation/resolution techniques based upon differences in solubility.
- separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof.
- stereoisomers are obtained by stereoselective synthesis.
- prodrugs refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility.
- a prodrug is a compound described herein, which is administered as an ester (the“prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
- a further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
- a prodrug upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
- a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
- prodrugs are designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
- some of the herein-described compounds may be a prodrug for another derivative or active compound.
- sites on the aromatic ring portion of compounds described herein are susceptible to various metabolic reactions Therefore incorporation of appropriate substituents on the aromatic ring structures will reduce, minimize or eliminate this metabolic pathway.
- the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, or an alkyl group.
- the compounds described herein are labeled isotopically (e.g., with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
- Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
- isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine such as, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl, and 125 I.
- isotopically-labeled compounds described herein for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
- substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
- the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
- “Pharmaceutically acceptable” as used herein refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
- the term“pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
- pharmaceutically acceptable salts are obtained by reacting a compound disclosed herein with acids.
- Pharmaceutically acceptable salts are also obtained by reacting a compound disclosed herein with a base to form a salt.
- compositions described herein may be formed as, and/or used as, pharmaceutically acceptable salts.
- pharmaceutical acceptable salts include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a
- inorganic acid such as, for example, hydrochloric acid
- hydrobromic acid sulfuric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid,
- cyclopentanepropionic acid glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1- carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,
- compounds described herein may coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine.
- compounds described herein may form salts with amino acids such as, but not limited to, arginine, lysine, and the like.
- Acceptable inorganic bases used to form salts with compounds that include an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
- a reference to a pharmaceutically acceptable salt includes the solvent addition forms, particularly solvates.
- Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein can be conveniently prepared or formed during the processes described herein.
- the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
- syntheses of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof.
- solvents, temperatures and other reaction conditions presented herein may vary.
- the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fisher Scientific (Fisher Chemicals), and Acros Organics.
- the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols.
- Alkyl refers to a straight or branched hydrocarbon chain radical, having from one to twenty carbon atoms, and which is attached to the rest of the molecule by a single bond.
- An alkyl comprising up to 10 carbon atoms is referred to as a C1-C10 alkyl, likewise, for example, an alkyl comprising up to 6 carbon atoms is a C1-C6 alkyl.
- Alkyls (and other moieties defined herein) comprising other numbers of carbon atoms are represented similarly.
- Alkyl groups include, but are not limited to, C1-C10 alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C2-C8 alkyl, C3-C8 alkyl and C4-C8 alkyl.
- alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, 1- ethyl-propyl, and the like.
- the alkyl is methyl or ethyl.
- an alkyl group may be optionally substituted as described below.
- Alkylene refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group.
- the alkylene is -CH2-, -CH2CH2-, or - CH 2 CH 2 CH 2 -.
- the alkylene is -CH 2 -.
- the alkylene is -CH 2 CH 2 -.
- the alkylene is -CH 2 CH 2 CH 2 -.
- Alkoxy refers to a radical of the formula -OR where R is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy. In some embodiments, the alkoxy is methoxy. In some embodiments, the alkoxy is ethoxy.
- “Heteroalkyl” refers to an alkyl radical as described above where one or more carbon atoms of the alkyl is replaced with a O, N (i.e., NH, N-alkyl) or S atom.
- “Heteroalkylene” refers to a straight or branched divalent heteroalkyl chain linking the rest of the molecule to a radical group. Unless stated otherwise specifically in the specification, the heteroalkyl or heteroalkylene group may be optionally substituted as described below. Representative heteroalkyl groups include, but are not limited to -OCH2OMe, -OCH2CH2OMe, or -OCH2CH2OCH2CH2NH2.
- heteroalkylene groups include, but are not limited to -OCH2CH2O-, - OCH 2 CH 2 OCH 2 CH 2 O-, or -OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 O-.
- Alkylamino refers to a radical of the formula -NHR or -NRR where each R is, independently, an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted as described below.
- aromatic refers to a planar ring having a delocalized ⁇ -electron system containing 4n+2 ⁇ electrons, where n is an integer. Aromatics can be optionally substituted.
- aromatic includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).
- Aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom.
- Aryl groups can be optionally substituted.
- aryl groups include, but are not limited to phenyl, and naphthyl. In some embodiments, the aryl is phenyl.
- an aryl group can be a monoradical or a diradical (i.e., an arylene group).
- the term“aryl” or the prefix“ar-” (such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted.
- “Carboxy” refers to -CO2H.
- carboxy moieties may be replaced with a“carboxylic acid bioisostere”, which refers to a functional group or moiety that exhibits similar physical and/or chemical properties as a carboxylic acid moiety.
- a carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group.
- a compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and/or biological properties when compared to the carboxylic acid-containing compound.
- a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group.
- bioisosteres of a carboxylic acid include, but are not limited to:
- Cycloalkyl refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. Cycloalkyls may be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms.
- cycloalkyls include, but are not limited to, cycloalkyls having from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or from three to five carbon atoms.
- Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- the monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
- the monocyclic cycloalkyl is cyclopentyl.
- Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, and 3,4-dihydronaphthalen-1(2H)-one. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted.
- fused refers to any ring structure described herein which is fused to an existing ring structure.
- fused ring is a heterocyclic ring or a heteroaryl ring
- any carbon atom on the existing ring structure which becomes part of the fused heterocyclic ring or the fused heteroaryl ring may be replaced with a nitrogen atom.
- Halo or“halogen” refers to bromo, chloro, fluoro or iodo.
- Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,
- haloalkyl group may be optionally substituted.
- Haloalkoxy refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy,
- haloalkoxy group may be optionally substituted.
- “Heterocycloalkyl” or“heterocyclyl” or“heterocyclic ring” refers to a stable 3- to 14-membered non-aromatic ring radical comprising 2 to 10 carbon atoms and from one to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
- the heterocycloalkyl radical may be a monocyclic, or bicyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems.
- the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized.
- the nitrogen atom may be optionally quaternized.
- the heterocycloalkyl radical is partially or fully saturated. Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,
- 2-oxopiperidinyl 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,
- heterocycloalkyl also includes all ring forms of
- heterocycloalkyls have from 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 8 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 8 carbons in the ring and 1 or 2 N atoms. In some embodiments, heterocycloalkyls have from 2 to 10 carbons, 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.
- heterocycloalkyls have from 2 to 10 carbons, 1-2 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl group may be optionally substituted.
- Heteroaryl refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
- the heteroaryl is monocyclic or bicyclic.
- Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quin
- monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
- bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8- naphthyridine, and pteridine.
- heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl.
- a heteroaryl contains 0-4 N atoms in the ring.
- a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C 1 -C 9 heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a C6-C9heteroaryl.
- the term“optionally substituted” or“substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C 1 -C 6 alkylalkyne, halogen, acyl, acyloxy, -CO 2 H, -CO 2 alkyl, nitro, and amino, including mono- and di-substituted amino groups (e.g., -NH2, -NHR, -NR2), and the protected derivatives thereof.
- additional group(s) individually and independently selected from alkyl, haloalkyl, cycloalky
- optional substituents are independently selected from alkyl, alkoxy, haloalkyl, cycloalkyl, halogen, -CN, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -OH, -CO 2 H, and -CO 2 alkyl.
- optional substituents are independently selected from fluoro, chloro, bromo, iodo, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3.
- substituted groups are substituted with one or two of the preceding groups.
- a "tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule.
- the compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
- co-administration or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
- an“effective amount” or“therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
- an“effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
- An appropriate“effective” amount in any individual case may be determined using techniques, such as a dose escalation study.
- an “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition).
- An example of an“effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a“therapeutically effective amount.”
- a “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
- a “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms.
- the full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
- a prophylactically effective amount may be administered in one or more administrations.
- An“activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist.
- A“function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman,
- the term“pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
- the term“fixed combination” means that the active ingredients, e.g., a compound of Formula (I) and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
- the term“non-fixed combination” means that the active ingredients, e.g., a compound of Formula (I) and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
- combination means that the active ingredients, e.g., a compound of Formula (I) and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
- active ingredients e.g., a compound of Formula (I) and a co-agent
- cocktail therapy e.g., the administration of three or more active ingredients.
- the term“subject” or“patient” encompasses mammals. Examples of mammals include, but are not limited to, humans. In one embodiment, the mammal is a human.
- the terms“treat,”“treating” or“treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
- the compounds described herein are formulated into pharmaceutical compositions.
- Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
- a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy,
- a pharmaceutical composition refers to a mixture of a compound disclosed herein with other chemical components (i.e., pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, or one or more combination thereof.
- the pharmaceutical composition facilitates administration of the compound to an organism.
- compositions described herein are administrable to a subject in a variety of ways by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injections), intranasal, buccal, topical or transdermal administration routes.
- parenteral e.g., intravenous, subcutaneous, intramuscular, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injections
- intranasal buccal
- topical or transdermal administration routes e.g., topical or transdermal administration routes.
- the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
- the compounds disclosed herein are administered orally.
- the compounds disclosed herein are administered topically.
- the compound disclosed herein is formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, rubs, smears, medicated sticks, medicated bandages, balms, creams or ointments.
- the compounds disclosed herein are administered topically to the skin.
- the compounds disclosed herein are administered by inhalation.
- the compounds disclosed herein are formulated for intranasal administration.
- Such formulations include nasal sprays, nasal mists, and the like.
- the compounds disclosed herein are formulated as eye drops.
- the effective amount of the compound disclosed herein is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by inhalation to the mammal; and/or (e) administered by nasal administration to the mammal; or and/or (f) administered by injection to the mammal; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to the mammal; and/or (j) administered non-systemically or locally to the mammal.
- any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound disclosed herein, including further embodiments in which (i) the compound is administered once; (ii) the compound is administered to the mammal multiple times over the span of one day; (iii) the compound is administered continually; or (iv) the compound is administered continuously.
- any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound disclosed herein, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours.
- the method comprises a drug holiday, wherein the administration of the compound disclosed herein is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed.
- the length of the drug holiday varies from 2 days to 1 year.
- the compound disclosed herein is administered in a local rather than systemic manner.
- the compound disclosed herein is administered topically. In some embodiments, the compound disclosed herein is administered systemically.
- the pharmaceutical formulation is in the form of a tablet. In other embodiments, pharmaceutical formulations of the compounds disclosed herein are in the form of a capsule.
- liquid formulation dosage forms for oral administration are in the form of aqueous suspensions or solutions selected from the group including, but not limited to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups.
- a compound disclosed herein is formulated for use as an aerosol, a mist or a powder.
- compositions may take the form of tablets, lozenges, or gels formulated in a conventional manner.
- compounds disclosed herein are prepared as transdermal dosage forms.
- a compound disclosed herein is formulated into a pharmaceutical composition suitable for intramuscular, subcutaneous, or intravenous injection.
- the compound disclosed herein is be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments.
- the compounds disclosed herein are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas.
- the compounds disclosed herein are used in the preparation of medicaments for the treatment of diseases or conditions described herein.
- a method for treating any of the diseases or conditions described herein in a subject in need of such treatment involves administration of pharmaceutical compositions that include at least one compound disclosed herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or solvate thereof, in therapeutically effective amounts to said subject.
- compositions containing the compound disclosed herein are administered for prophylactic and/or therapeutic treatments.
- the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial.
- compositions containing the compounds disclosed herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.
- the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a“drug holiday”).
- Doses employed for adult human treatment are typically in the range of 0.01mg-5000 mg per day or from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses.
- a compound disclosed herein is co-administered with a second therapeutic agent, wherein the compound disclosed herein and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
- dosages of the co-administered compounds vary depending on the type of co-drug(s) employed, on the specific drug(s) employed, on the disease or condition being treated and so forth.
- the compound provided herein when co-administered with one or more other therapeutic agents, is administered either simultaneously with the one or more other therapeutic agents, or sequentially.
- the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms.
- the present disclosure provides a method of agonizing a G protein coupled receptor in a cell, the method comprising contacting the cell with any one of compounds described herein, or a pharmaceutically acceptable salt thereof.
- the present disclosure provides a method of promoting YAP phosphorylation in a cell, the method comprising contacting the cell with any one of compounds described herein, or a pharmaceutically acceptable salt thereof.
- agonism of the G protein coupled receptor results in YAP/TAZ phosphorylation and subsequent degradation.
- the present disclosure provides a method of inhibiting YAP/TAZ function in a cell (e.g., inhibiting expression of a profibrotic gene in a cell), the method comprising contacting the cell with any one of the compounds of the present disclosure, or a pharmaceutically acceptable salt thereof.
- agonism of the G protein coupled receptor results in inhibition of YAP/TAZ function in a cell and subsequent inhibition of expression of profibrotic genes in the cell.
- inhibiting YAP/TAZ function in a cell results in prevention of accumulation of extracellular matrix in a tissue.
- agonism of G protein coupled receptor reverses fiber formation and extracellular matrix accumulation.
- the fiber formation is induced by trauma or tissue injury. Normally cells generate just the right amount of tissue to replace old tissue or repair damage. Excessive connective tissue generation (e.g., in response to trauma or injury) results in pathological accumulation of fibrotic tissue (e.g., extracellular matrix proteins) leading to organ or tissue thickening and scarring.
- the present disclosure provides a method of treating a disease or condition in a mammal that would benefit from inhibition of YAP/TAZ activity, comprising administering to the mammal a compound as disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
- the present disclosure provides a method of treating or preventing a fibrotic pathology in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of any one of the compounds described herein, or a pharmaceutically acceptable salt thereof.
- the subject in need of treatment of fibrotic pathology is diagnosed with fibrotic pathology by a treating physician.
- the fibrotic pathology is interstitial lung disease (ILD).
- fibrotic pathology is lung tissue fibrosis, e.g., pulmonary fibrosis (PF) or idiopathic pulmonary fibrosis (IPF).
- PF pulmonary fibrosis
- IPF idiopathic pulmonary fibrosis
- cystic fibrosis is not considered an interstitial lung disease or predominantly a fibrotic pathology. Cystic fibrosis results from impaired ion transport, mucus dysfunction, and failure to effectively clear pathogens from the airways, which eventually results in scarring of the airways and lungs.
- fibrotic pathology is a liver tissue fibrosis, e.g., cirrhosis or biliary atresia.
- fibrotic pathology is a heart tissue fibroses (cardiac fibrosis), e.g., atrial fibrosis, endomyocardial fibrosis, or post-myocardial infarction scarring.
- fibrotic pathology is a brain tissue fibrosis, e.g., glial scar.
- fibrotic pathology is arterial stiffness, arthrofibrosis (knee, shoulder, elbow, or other joints), chronic kidney disease and fibrosis, liver fibrosis, nonalcoholic fatty liver, nonalcoholic steatohepatitis, Crohn's disease (intestinal scarring), Dupuytren’s contracture (scar tissue in hands or fingers), skin tissue fibrosis, e.g., keloid (a scar on the skin), mediastinal fibrosis (soft tissue of the mediastinum), Peyronie’s disease (scar in a penial tissue), nephrogenic systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis (scar on the soft tissue of the retroperitoneum) or adhesive capsulitis.
- tissue injury include injury caused by inhaled substances (e.g., silica or asbestos), drug-induced injury (injury caused by an antibiotic or an anticancer drug), tissue injury caused by autoimmune disease (e.g., rheumatoid arthritis, sclerosis, such as systemic sclerosis, lupus), injury caused by infection (e.g., tuberculosis, pneumonia, respiratory virus), or sarcoidosis.
- inhaled substances e.g., silica or asbestos
- drug-induced injury injury caused by an antibiotic or an anticancer drug
- tissue injury caused by autoimmune disease e.g., rheumatoid arthritis, sclerosis, such as systemic sclerosis, lupus
- infection e.g., tuberculosis, pneumonia, respiratory virus
- sarcoidosis e.g., tuberculosis, pneumonia, respiratory virus
- HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
- Ms Mesyl, or methanesulfonyl
- PE Petroleum ether
- TFA Trifluoroacetic acid Examples 1 and 2: Synthesis of (6aR,12bR)-5,6,6a,7,8,12b- hexahydrobenzo[a]phenanthridine-3,4,10,11-tetraol (Compound and (6aR,12bS)-
- Isomer 2 was further purified by prep-HPLC (AcONH4) to give AcOH salt of cis- (6a,12b)-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-3,4,10,11-tetraol (2.2 mg, yield: 9%) as a yellow solid.
- Example 4 Synthesis of (6aR,12bS)-10,11-dimethoxy-2-methyl-5,6,6a,7,8,12b- hexahydrobenzo[a]phenanthridin-3-ol (Compound 4a) and (6aS,12bR)-10,11-dimethoxy-2- methyl-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridin-3-ol (Compound 4b)
- trans-(6aR,12bS)-3,10,11-trimethoxy-2-methyl-5,6,6a,7,8,12b- hexahydrobenzo[a]phenanthridine 450 mg, 1.33 mmol
- (6aR,12bS)-3,10,11-trimethoxy-2-methyl-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine 160 mg, yield 36%) as a white solid.
- trans-(6a,12b)-2-methyl-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-3,10,11-triol 150 mg, 0.51 mmol
- (6aR,12bS)-10,11-dimethoxy-2- methyl-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridin-3-ol 25 mg, yield: 17%) as a light yellow solid.
- Example A-1 Parenteral Pharmaceutical Composition
- a parenteral pharmaceutical composition suitable for administration by injection e.g., subcutaneous or intravenous
- 1-1000 mg of a water-soluble salt of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline.
- a suitable buffer is optionally added as well as optional acid or base to adjust the pH.
- the mixture is incorporated into a dosage unit form suitable for administration by injection.
- Example A-2 Oral Solution
- a tablet is prepared by mixing 20-50% by weight of a compound described herein, or a pharmaceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of low-substituted hydroxypropyl cellulose, and 1-10% by weight of magnesium stearate or other appropriate excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100 -500 mg.
- Example A-4 Oral Capsule
- a pharmaceutical composition for oral delivery 1-1000 mg of a compound described herein, or a pharmaceutically acceptable salt thereof, is mixed with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.
- Cell culture Cells are maintained in EMEM (ATCC) containing 10% FBS. IMR-90 embryonic lung fibroblasts and NIH-3T3 mouse fibroblasts are purchased from ATCC.
- Normal Human Alveolar Epithelial Cells (NHAEpCs), Normal Human Microvascular Endothelial Cells (NHMVECs), Normal Human Lung Fibroblasts (NHLFs), and Human Dermal Fibroblasts (HDFs) are purchased from Lonza and are cultured in the proprietary media per Lonza’s recommendation.
- Human Adult Cardiac Fibroblasts (HACFs) and Hepatic Stellate Cells (HSCs) are purchased from ScienCell and are cultured in the proprietary media per ScienCell’s recommendation.
- Hepatocytes are purchased from Samsara and are cultured in the proprietary media per Samsara’s recommendation. All additional experiments with pulmonary fibroblasts are primary human lung fibroblasts isolated by explant culture from the lungs of subjects diagnosed with IPF who underwent lung transplantation, or donors whose organs were rejected for transplantation (non-IPF), generously provided by Peter Bitterman and Craig Henke at the University of Minnesota under a protocol approved by the University of Minnesota Institutional Review Board. All primary cell culture experiments are performed with cells at passage six or less.
- GPC Rome profiling is performed according to the manufacturer’s suggestions (Qiagen). Cells are grown in their recommended growth media for 24 hours prior to RNA isolation using RNeasy Plus Mini Kit (Qiagen) according to manufacturer’s instructions. Isolated RNA (1000 ng) are then used to synthesize cDNA using the RT 2 First Strand Kit (Qiagen) and the G Protein Coupled Receptors 384HT PCR Array is analyzed using a LightCycler 480 (Roche).
- FACS sorting is conducted using a BD FACS Aria II (BD Biosciences).
- FACS-sorted epithelial cells, endothelial cells and fibroblasts are collected in 1.5 mL Eppendorf tubes containing RLT lysis buffer (Qiagen), which is subjected to mRNA extraction, complementary DNA synthesis and RT–PCR analysis.
- MACS/PBS perfused mouse lungs is finely minced with a razor blade in a 100 mm petri dish in 1 mL of MACs dissociation solution described in the MACS mouse lung dissociation kit. The mixture is then transferred to 15 mL tubes and incubated at 37 °C for 30 min in a water bath. Enzymatic digestion is inactivated by adding DMEM containing 10% fetal bovine serum.
- the cell suspension is passed once through a 40 ⁇ m cell strainer (Fisher) to remove multicellular debris. Cells are then centrifuged at 1,350 r.p.m. at 4 °C for 10 min and the supernatant is aspirated. The samples are resuspended in 0.1ml 15% BSA-autoMACS rinsing solution. The single cell suspension is than incubated with mouse anti-CD45 MicroBeads (1:10) for 15 minutes at 4-8 °C. Cells are then magnetically filtered using LS column (Miltenyi Biotec). Positively selected cells are pelleted at 1350 r.p.m at 4 °C and resuspended in RLT lysis buffer (Qiagen).
- LS column Miltenyi Biotec
- Cells or tissue sections are incubated overnight with mouse monoclonal antibody against aSMA (Sigma-Aldrich F3777), and/or a rabbit monoclonal antibody against YAP/TAZ (Cell Signaling D24E4) diluted 1:200 in PBS with 1% BSA. Cells are then washed and exposed to flourescence- conjugated secondary antibodies (Invitrogen) diluted 1:1000 and DAPI (Thermo Fisher
- YAP/TAZ localization is quantified using Gen5 (Biotek) software. Images are taken at 4X magnification of both DAPI and YAP/TAZ staining.
- Traction Force Microscopy Traction analysis is conducted. Polyacrylamide substrates with shear moduli of 6.4 kPa are prepared, and fluorescent sulfate-modified latex microspheres (0.2 mm, 505/515ex/em) (FluoSpheres, Life Technologies) is conjugated to the gel surfaces after treatment with 1 mg/ml-1 of dopamine hydrochloride (Sigma-Aldrich) in 50 mM HEPES solution (pH 8.5). IPF patient derived fibroblasts are plated on the gels overnight and treated as indicated before traction force measurements.
- dopamine hydrochloride Sigma-Aldrich
- cAMP Assay IPF patient derived fibroblasts are plated in EMEM containing 10% FBS overnight. Media is exchanged with EMEM containing 0.1% FBS for 24 hours. cAMP is measured using the cAMP-GloTM Assay (Promega) according to manufacturer’s suggestions. Twenty minutes prior to cell lysis the media is removed and cells are treated with“induction buffer” containing nonselective phosphodiesterase inhibitors and the indicated concentration of compound(s). Luminescence is measured on a Flexstation 3 (Molecular Devices) plate reader.
- Blots are incubated overnight with primary antibodies: pYAP (Ser 127, Cell Signaling D9W21), YAP/TAZ (Cell Signaling D24E4), GAPDH (Cell Signaling 14C10), HSC70 (Santa Cruz sc- 7298), aSMA (Abcam ab5694), and fibronectin (Santa Cruz sc-9068) diluted 1:1000 in Li-Cor Odyssey Blocking Buffer. Blots are washed with TBS-Tween before 60 minute incubation with IR-dye-conjugated secondary antibodies (Li-Cor) diluted 1:10,000. Plates are imaged via a Li- Cor OdysseyXL system with quantification performed via densitometry.
- Immuno-ECM Adapting from previously published methods, IPF patient-derived fibroblasts are plated to confluence in clear-bottom 96-well plates. After cells attached, the medium is swapped for EMEM containing 0.1% FBS ⁇ 2 ng/mL TGF-b. After 48 hrs the indicated concentration of DHX or DMSO control is added to each well and incubated for 24 hrs. WST-1 viability reagent is added to each well (Sigma-Aldrich) and measured on a Flexstation 3 (Molecular Devices) plate reader. Cells are then fixed in 3.7% formalin (Sigma-Aldrich), and permeabilized in 0.25% Triton X-100 (Sigma-Aldrich).
- Wells are next washed with tris-buffered saline (TBS) and blocked with Li-Cor Odyssey Blocking Buffer for 60 minutes before overnight incubation in a polyclonal rabbit antibody for fibronectin (Sigma sc-9068) or collagen I (Novus NB600-408) diluted 1:200 in blocking buffer.
- Wells are washed with TBS-Tween before 45 minute incubation with IR-dye-conjugated secondary antibody (Li-Cor #926-32211) diluted 1:400. Plates are imaged via a Li-Cor OdysseyXL system with quantification performed via densitometry. Data is expressed as IR intensity relative to WST-1 signal absorbance in order to account for any potential compound toxicity.
- Matrix Remodeling Measured by Atomic Force Microscopy NIH-3T3 cells are plated to confluence onto gelatin coated (Cell Biologics) AFM compatible tissue culture dishes (Willco) in DMEM containing 10% FBS. After cells attached overnight, media is replaced with DMEM containing 2% FBS, 2 ng/mL TGFf3, and 20 ⁇ g/mL ascorbic acid to promote matrix deposition. After 72 hrs, measurements are made using a BioScope Catalyst AFM (Bruker, MA, USA).
- Microindentations are performed using a 2.5 ⁇ m radius sphere-tipped probe (Novascan, IA, USA) with a spring constant determined at ⁇ 100 pN nm-1 by thermal fluctuation method. For each dish, 3 different areas are analyzed. Force curves are acquired with MIRO 2.0 (NanoScope 9.1; Bruker) at an indentation rate of 20 mm s-1 and a ramp size of 10 mm on different points. The Young’s modulus E is determined by the fitting of force curve by Hertz model using NanoScope Analysis software (Bruker) and considering Poisson’s ratio of 0.5.
- RNA Interference Cells are transfected using Lipofectamine RNAiMAX (Life Technologies).
- siGENOME siRNA SMARTpool Dharmacon
- DRD1 L- 005477-00-0005
- nontargeting SMARTpool D-001810-10 ⁇ 05
- Cells are cultured for 72 hrs before collecting RNA.
- the cells are transfected in their 6-well plates for 48 hrs prior to re-plating into 96-well plates for the immunofluorescence assays.
- mice were anesthetized with ketamine and xylazine before exposure of the trachea. Lung fibrosis is induced by intratracheal injection of bleomycin (50 mL at 1.2 U/kg) or phosphate buffered saline (PBS; as control) on day 0.
- bleomycin 50 mL at 1.2 U/kg
- PBS phosphate buffered saline
- siRNA duplexes targeting mouse YAP (L-046247-01-0005) or TAZ (L-058248-01-0005) mRNA (Dharmacon) or nontargeting control siRNA are administered in vivo by intratracheal instillation at a single dose of 25 mg (each siRNA) per mouse.
- BAL samples for total protein concentration determination, lungs were lavaged with six 0.5-mL aliquots of PBS. BAL samples were centrifuged at 3,000g for 20 min at 4 °C and the supernatants is transferred to siliconized low- binding Eppendorf tubes (PGC Scientifics) for subsequent analysis. Total protein concentration of the BAL fluid was determined by BCA Protein Assay Kit (Pierce).
- H&E hematoxylin and eosin
- Abcam Masson’s Trichrome stain kit
- All H&E-stained slides and trichrome-stained slides were reviewed in a blinded fashion by a thoracic pathologist.
- the severity of interstitial and peribronchiolar lung immature and mature fibrosis was estimated on a numerical scale according to Ashcroft et al. For scoring purposes, all H&E stained slides were systematically scanned at 100X magnification and successive 100X fields were be scored.
- Scoring was based on the following scale: 0 (no fibrosis), 1 (minimal interstitial and/or peribronchiolar thickening due to fibrosis), 3 (moderate thickening without obvious architectural distortion), 5 (increased fibrosis with formation of fibrous bands and/or small masses), 7 (severe architectural distortion with large areas of fibrosis and areas of honeycomb changes), and 8 (total fibrous obliteration of the field). Liver trichrome stained sections were computationally measured using Image J software. After converting each image in an RGB stack, the threshold was adjusted and kept at the same level for all the images.
- Hydroxyproline Hydroxyproline content was measured using a hydroxyproline assay kit (Biovision) according to the manufacture’s instruction.
- the lung tissues was weighed, homogenized in sterile water (10 mg of tissue per 100 mL H 2 O) and hydrolyzed in 12N HCl in a pressure-tight, Teflon-capped vial at 120 °C for 3 hrs followed by filtration through a 45 mm Spin-X® Centrifuge Tube filter (Corning).
- Compound 3 inhibits expression of Col1a1 in precision cut lung slices cultured for 3 days from aged mice (24 months) injured with bleomycin. (10 ⁇ M
- Example B-1 Enzyme assay of inhibition of YAP/TAZ and DR1
- IC50/EC50 is £ 1 ⁇ M
- B IC50/EC50 is > 1 ⁇ M and £ 20 ⁇ M
- C IC50/EC50 > 20 ⁇ M (a compound that is active).
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Biomedical Technology (AREA)
- Physical Education & Sports Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201962880604P | 2019-07-30 | 2019-07-30 | |
PCT/US2020/044099 WO2021021953A2 (en) | 2019-07-30 | 2020-07-29 | Dopamine receptor d1 agonists and methods of use |
Publications (2)
Publication Number | Publication Date |
---|---|
EP4003339A2 true EP4003339A2 (en) | 2022-06-01 |
EP4003339A4 EP4003339A4 (en) | 2023-02-22 |
Family
ID=74230823
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP20846249.9A Pending EP4003339A4 (en) | 2019-07-30 | 2020-07-29 | Dopamine receptor d1 agonists and methods of use |
Country Status (3)
Country | Link |
---|---|
US (1) | US20220267277A1 (en) |
EP (1) | EP4003339A4 (en) |
WO (1) | WO2021021953A2 (en) |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2927294A1 (en) * | 1979-07-06 | 1981-01-08 | Boehringer Sohn Ingelheim | NEW 4-PHENYL-4,5,6,7-TETRAHYDROPYRROLO ANGLE CLAMP ON 2.3-C ANGLE CLAMP FOR PYRIDINE, METHOD FOR THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS |
CA2195239A1 (en) * | 1994-07-15 | 1996-02-01 | David E. Nichols | Optically active isomers of dihydrexidine and its substituted analogs |
US5668141A (en) * | 1996-04-02 | 1997-09-16 | Abbott Laboratories | Trans-2,6-,3,6-and 4,6-diaza-5,6,6a,7,8,12b-hexahydrobenzo[c]phenanthrene compounds as dopamine agonists |
EP2364317B1 (en) * | 2008-08-05 | 2015-07-29 | Effipharma, Inc. | Dopamine receptor ligands with enhanced duration of action |
EP3661512A4 (en) * | 2017-07-31 | 2020-12-30 | The Regents of the University of California | Anti-cancer/anti-fibrosis compounds |
-
2020
- 2020-07-29 US US17/628,875 patent/US20220267277A1/en active Pending
- 2020-07-29 WO PCT/US2020/044099 patent/WO2021021953A2/en unknown
- 2020-07-29 EP EP20846249.9A patent/EP4003339A4/en active Pending
Also Published As
Publication number | Publication date |
---|---|
WO2021021953A3 (en) | 2021-03-25 |
EP4003339A4 (en) | 2023-02-22 |
WO2021021953A2 (en) | 2021-02-04 |
US20220267277A1 (en) | 2022-08-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6493890B2 (en) | Inhibitors of lysine-specific demethylase-1 | |
JP4054368B2 (en) | Substituted methylaryl or heteroarylamide compounds | |
EP1263732A1 (en) | Corticotropin releasing factor antagonists | |
WO2012012322A1 (en) | Substituted hydroxamic acids and uses thereof | |
CN115232129B (en) | PARP1 selective inhibitor and preparation method and application thereof | |
WO2022060951A1 (en) | Compositions for modulating splicing | |
CA3194694A1 (en) | Acetamido-phenyltetrazole derivatives and methods of using the same | |
JP2022545326A (en) | Heterocyclic compound, method for producing the same and method for using the same | |
TW202216697A (en) | Compositions for modulating splicing | |
EP4003339A2 (en) | Dopamine receptor d1 agonists and methods of use | |
US7589205B2 (en) | 3-thia-10-aza-phenanthrene derivatives | |
NO180230B (en) | 2-amino-1,2,3,4-tetrahydronaphthalene derivatives with cardiovascular activity and pharmaceutical preparations containing such | |
EP1797098B1 (en) | 3-oxa-10-aza-phenanthrenes as pde4 or pde3/4 inhibitors | |
JP2010526051A (en) | N- [6-amino-5- (phenyl) pyrazin-2-yl] -isoxazole-4-carboxamide derivatives and related compounds as NAV1.8 channel modulators for the treatment of pain | |
CA2541162A1 (en) | Fused lactam compounds | |
EP4320117A2 (en) | Novel hepatoselective polyadenylating polymerases inhibitors and their method of use | |
CA2540083A1 (en) | Imidazopyridine-derivatives as inductible no-synthase inhibitors | |
CA2200324C (en) | 4a-aryldecahydroisoquinoline compounds and medicinal use of the same | |
KR102253721B1 (en) | Benzothiophene compound | |
JPWO2005061508A1 (en) | Tricyclic heterocyclic compounds and pharmaceuticals containing the compounds as active ingredients | |
AU2020349516A1 (en) | Substituted imidazole carboxamides and their use in the treatment of medical disorders | |
WO2023177593A1 (en) | Phenyl triazole mll1-wdr5 protein-protein interaction inhibitor | |
WO2022060944A1 (en) | Compositions for modulating splicing | |
JPH05239030A (en) | Aminomethyltetrahydroisoquinoline derivative and its production |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20220127 |
|
AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) | ||
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R079 Free format text: PREVIOUS MAIN CLASS: A61K0031435000 Ipc: C07D0221020000 |
|
A4 | Supplementary search report drawn up and despatched |
Effective date: 20230120 |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: A61P 17/00 20060101ALI20230116BHEP Ipc: A61P 11/00 20060101ALI20230116BHEP Ipc: A61P 9/00 20060101ALI20230116BHEP Ipc: A61P 1/00 20060101ALI20230116BHEP Ipc: A61K 31/4375 20060101ALI20230116BHEP Ipc: A61K 31/4353 20060101ALI20230116BHEP Ipc: A61K 31/435 20060101ALI20230116BHEP Ipc: C07D 221/18 20060101ALI20230116BHEP Ipc: C07D 221/04 20060101ALI20230116BHEP Ipc: C07D 221/02 20060101AFI20230116BHEP |
|
P01 | Opt-out of the competence of the unified patent court (upc) registered |
Effective date: 20230502 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
17Q | First examination report despatched |
Effective date: 20231219 |